US20230096528A1 - Pharmaceutical Composition for Treatment or Prevention of Multiple Inflammatory disorders - Google Patents
Pharmaceutical Composition for Treatment or Prevention of Multiple Inflammatory disorders Download PDFInfo
- Publication number
- US20230096528A1 US20230096528A1 US17/845,399 US202217845399A US2023096528A1 US 20230096528 A1 US20230096528 A1 US 20230096528A1 US 202217845399 A US202217845399 A US 202217845399A US 2023096528 A1 US2023096528 A1 US 2023096528A1
- Authority
- US
- United States
- Prior art keywords
- denatonium
- group
- salt
- treatment
- adult
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 127
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 28
- 230000002265 prevention Effects 0.000 title claims abstract description 25
- 208000027866 inflammatory disease Diseases 0.000 title claims abstract description 12
- VWTINHYPRWEBQY-UHFFFAOYSA-N denatonium Chemical class [O-]C(=O)C1=CC=CC=C1.C=1C=CC=CC=1C[N+](CC)(CC)CC(=O)NC1=C(C)C=CC=C1C VWTINHYPRWEBQY-UHFFFAOYSA-N 0.000 claims abstract description 149
- 229940006275 denatonium Drugs 0.000 claims abstract description 82
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims abstract description 47
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims abstract description 46
- 208000001145 Metabolic Syndrome Diseases 0.000 claims abstract description 44
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 42
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims abstract description 35
- 102000016267 Leptin Human genes 0.000 claims abstract description 29
- 108010092277 Leptin Proteins 0.000 claims abstract description 29
- 208000008589 Obesity Diseases 0.000 claims abstract description 29
- 229940039781 leptin Drugs 0.000 claims abstract description 29
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 claims abstract description 29
- 230000037361 pathway Effects 0.000 claims abstract description 29
- 235000020824 obesity Nutrition 0.000 claims abstract description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims abstract description 27
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 25
- 206010009900 Colitis ulcerative Diseases 0.000 claims abstract description 21
- 208000011231 Crohn disease Diseases 0.000 claims abstract description 21
- 201000006704 Ulcerative Colitis Diseases 0.000 claims abstract description 21
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 20
- 230000001684 chronic effect Effects 0.000 claims abstract description 19
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 19
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 18
- 206010025135 lupus erythematosus Diseases 0.000 claims abstract description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims abstract description 17
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 17
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims abstract description 17
- 229940095064 tartrate Drugs 0.000 claims abstract description 17
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 17
- 206010007559 Cardiac failure congestive Diseases 0.000 claims abstract description 16
- 206010019280 Heart failures Diseases 0.000 claims abstract description 16
- 206010020772 Hypertension Diseases 0.000 claims abstract description 16
- 206010020710 Hyperphagia Diseases 0.000 claims abstract description 15
- 208000037979 autoimmune inflammatory disease Diseases 0.000 claims abstract description 15
- 201000001421 hyperglycemia Diseases 0.000 claims abstract description 15
- 230000001404 mediated effect Effects 0.000 claims abstract description 12
- 230000007812 deficiency Effects 0.000 claims abstract description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 49
- 239000000203 mixture Substances 0.000 claims description 18
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 15
- 230000005713 exacerbation Effects 0.000 claims description 13
- DMRHOZBCVOAFHR-UHFFFAOYSA-N benzyl-[2-(2,6-dimethylanilino)-2-oxoethyl]-diethylazanium 1-oxido-1-oxo-1,2-benzothiazol-3-one Chemical compound CC[N+](CC)(CC1=CC=CC=C1)CC(=O)NC2=C(C=CC=C2C)C.C1=CC=C2C(=C1)C(=O)N=S2(=O)[O-] DMRHOZBCVOAFHR-UHFFFAOYSA-N 0.000 claims description 12
- 230000002685 pulmonary effect Effects 0.000 claims description 5
- 230000001154 acute effect Effects 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 48
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 abstract description 45
- 201000010099 disease Diseases 0.000 abstract description 26
- 239000000090 biomarker Substances 0.000 abstract description 24
- 208000035475 disorder Diseases 0.000 abstract description 21
- 230000011664 signaling Effects 0.000 abstract description 15
- 201000010769 Prader-Willi syndrome Diseases 0.000 abstract description 10
- 208000033489 Syndromic obesity Diseases 0.000 abstract description 10
- 208000037493 inherited obesity Diseases 0.000 abstract description 10
- 230000000770 proinflammatory effect Effects 0.000 abstract description 10
- 208000037976 chronic inflammation Diseases 0.000 abstract description 6
- 229940088597 hormone Drugs 0.000 abstract description 6
- 239000005556 hormone Substances 0.000 abstract description 6
- 230000004968 inflammatory condition Effects 0.000 abstract description 5
- 208000037893 chronic inflammatory disorder Diseases 0.000 abstract description 4
- 230000004044 response Effects 0.000 abstract description 4
- 241000699670 Mus sp. Species 0.000 description 62
- 102000004127 Cytokines Human genes 0.000 description 59
- 108090000695 Cytokines Proteins 0.000 description 59
- 210000004369 blood Anatomy 0.000 description 48
- 239000008280 blood Substances 0.000 description 48
- 230000002354 daily effect Effects 0.000 description 39
- 230000000694 effects Effects 0.000 description 37
- 210000002966 serum Anatomy 0.000 description 31
- 241001465754 Metazoa Species 0.000 description 29
- 230000007423 decrease Effects 0.000 description 28
- 230000003247 decreasing effect Effects 0.000 description 27
- 230000037396 body weight Effects 0.000 description 26
- 239000003814 drug Substances 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 229940079593 drug Drugs 0.000 description 22
- 239000002158 endotoxin Substances 0.000 description 22
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 22
- 229920006008 lipopolysaccharide Polymers 0.000 description 21
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 18
- 238000004458 analytical method Methods 0.000 description 17
- 239000002775 capsule Substances 0.000 description 16
- 210000000416 exudates and transudate Anatomy 0.000 description 16
- 206010061218 Inflammation Diseases 0.000 description 15
- 108090001005 Interleukin-6 Proteins 0.000 description 15
- 102000004889 Interleukin-6 Human genes 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 230000004054 inflammatory process Effects 0.000 description 15
- 102000003814 Interleukin-10 Human genes 0.000 description 14
- 108090000174 Interleukin-10 Proteins 0.000 description 14
- 238000003304 gavage Methods 0.000 description 14
- 108090000623 proteins and genes Proteins 0.000 description 14
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 13
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 13
- 102000015779 HDL Lipoproteins Human genes 0.000 description 13
- 108010010234 HDL Lipoproteins Proteins 0.000 description 13
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical class CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 13
- 102000004169 proteins and genes Human genes 0.000 description 13
- 208000031648 Body Weight Changes Diseases 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 12
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 12
- 230000004579 body weight change Effects 0.000 description 12
- 210000004072 lung Anatomy 0.000 description 12
- 230000004060 metabolic process Effects 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 12
- 102000004877 Insulin Human genes 0.000 description 11
- 108090001061 Insulin Proteins 0.000 description 11
- 239000012530 fluid Substances 0.000 description 11
- 229940125396 insulin Drugs 0.000 description 11
- 239000008188 pellet Substances 0.000 description 11
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 10
- 102000007330 LDL Lipoproteins Human genes 0.000 description 10
- 108010007622 LDL Lipoproteins Proteins 0.000 description 10
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 10
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 10
- 102100040247 Tumor necrosis factor Human genes 0.000 description 10
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 10
- 206010012601 diabetes mellitus Diseases 0.000 description 10
- 230000002550 fecal effect Effects 0.000 description 10
- 239000008103 glucose Substances 0.000 description 10
- 238000001727 in vivo Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 9
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 9
- 108010002616 Interleukin-5 Proteins 0.000 description 9
- 238000011161 development Methods 0.000 description 9
- 235000012631 food intake Nutrition 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 102100025248 C-X-C motif chemokine 10 Human genes 0.000 description 8
- 241000711573 Coronaviridae Species 0.000 description 8
- 108050003558 Interleukin-17 Proteins 0.000 description 8
- 102000013691 Interleukin-17 Human genes 0.000 description 8
- 108010002350 Interleukin-2 Proteins 0.000 description 8
- 102000000588 Interleukin-2 Human genes 0.000 description 8
- 101710151803 Mitochondrial intermediate peptidase 2 Proteins 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 8
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 8
- 239000003613 bile acid Substances 0.000 description 8
- 230000002068 genetic effect Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 150000003626 triacylglycerols Chemical class 0.000 description 8
- 239000004475 Arginine Substances 0.000 description 7
- 102100036170 C-X-C motif chemokine 9 Human genes 0.000 description 7
- 101710085500 C-X-C motif chemokine 9 Proteins 0.000 description 7
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 7
- 239000004472 Lysine Substances 0.000 description 7
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 7
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 7
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 7
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 7
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 7
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 7
- 230000015556 catabolic process Effects 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 238000006731 degradation reaction Methods 0.000 description 7
- 235000005911 diet Nutrition 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 7
- 230000006698 induction Effects 0.000 description 7
- 230000002757 inflammatory effect Effects 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 244000005700 microbiome Species 0.000 description 7
- 238000010172 mouse model Methods 0.000 description 7
- 210000000440 neutrophil Anatomy 0.000 description 7
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 7
- 229960003104 ornithine Drugs 0.000 description 7
- 150000003905 phosphatidylinositols Chemical class 0.000 description 7
- 239000000454 talc Substances 0.000 description 7
- 229910052623 talc Inorganic materials 0.000 description 7
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 7
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 7
- 101710098275 C-X-C motif chemokine 10 Proteins 0.000 description 6
- 208000024172 Cardiovascular disease Diseases 0.000 description 6
- 102100023688 Eotaxin Human genes 0.000 description 6
- 101710139422 Eotaxin Proteins 0.000 description 6
- 102100034221 Growth-regulated alpha protein Human genes 0.000 description 6
- 101001069921 Homo sapiens Growth-regulated alpha protein Proteins 0.000 description 6
- -1 IFNγ Proteins 0.000 description 6
- 108010065805 Interleukin-12 Proteins 0.000 description 6
- 102000013462 Interleukin-12 Human genes 0.000 description 6
- 102000003816 Interleukin-13 Human genes 0.000 description 6
- 108090000176 Interleukin-13 Proteins 0.000 description 6
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 6
- 238000009825 accumulation Methods 0.000 description 6
- 235000021342 arachidonic acid Nutrition 0.000 description 6
- 229940114079 arachidonic acid Drugs 0.000 description 6
- 230000034659 glycolysis Effects 0.000 description 6
- 230000000813 microbial effect Effects 0.000 description 6
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 5
- 108010002386 Interleukin-3 Proteins 0.000 description 5
- 102000000646 Interleukin-3 Human genes 0.000 description 5
- 108090000978 Interleukin-4 Proteins 0.000 description 5
- 102000004388 Interleukin-4 Human genes 0.000 description 5
- 241000700605 Viruses Species 0.000 description 5
- 210000000577 adipose tissue Anatomy 0.000 description 5
- 230000003143 atherosclerotic effect Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 206010009887 colitis Diseases 0.000 description 5
- 210000001072 colon Anatomy 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 230000034994 death Effects 0.000 description 5
- 231100000517 death Toxicity 0.000 description 5
- 230000002950 deficient Effects 0.000 description 5
- 230000037213 diet Effects 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 231100000673 dose–response relationship Toxicity 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 230000001200 fecal consistency Effects 0.000 description 5
- 230000004110 gluconeogenesis Effects 0.000 description 5
- 235000009200 high fat diet Nutrition 0.000 description 5
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 5
- 238000007912 intraperitoneal administration Methods 0.000 description 5
- 210000002540 macrophage Anatomy 0.000 description 5
- 208000030159 metabolic disease Diseases 0.000 description 5
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 5
- 238000010149 post-hoc-test Methods 0.000 description 5
- 150000004666 short chain fatty acids Chemical class 0.000 description 5
- 230000009885 systemic effect Effects 0.000 description 5
- 230000004580 weight loss Effects 0.000 description 5
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 4
- 108010055166 Chemokine CCL5 Proteins 0.000 description 4
- 241000192125 Firmicutes Species 0.000 description 4
- 206010020843 Hyperthermia Diseases 0.000 description 4
- 108010002586 Interleukin-7 Proteins 0.000 description 4
- 206010035664 Pneumonia Diseases 0.000 description 4
- 241000192142 Proteobacteria Species 0.000 description 4
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 4
- 241001261005 Verrucomicrobia Species 0.000 description 4
- 238000000540 analysis of variance Methods 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- 230000037406 food intake Effects 0.000 description 4
- 210000003714 granulocyte Anatomy 0.000 description 4
- 230000036031 hyperthermia Effects 0.000 description 4
- 210000002865 immune cell Anatomy 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 210000000265 leukocyte Anatomy 0.000 description 4
- 210000004698 lymphocyte Anatomy 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 230000002503 metabolic effect Effects 0.000 description 4
- 230000037340 metabolism of cofactors and vitamins Effects 0.000 description 4
- 210000001616 monocyte Anatomy 0.000 description 4
- 238000002203 pretreatment Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 210000000952 spleen Anatomy 0.000 description 4
- 210000005167 vascular cell Anatomy 0.000 description 4
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 3
- 208000004611 Abdominal Obesity Diseases 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 3
- 208000025721 COVID-19 Diseases 0.000 description 3
- 241000192700 Cyanobacteria Species 0.000 description 3
- 241001143296 Deferribacteres <phylum> Species 0.000 description 3
- 206010061818 Disease progression Diseases 0.000 description 3
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 3
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 3
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 3
- 102400000326 Glucagon-like peptide 2 Human genes 0.000 description 3
- 101800000221 Glucagon-like peptide 2 Proteins 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 206010021143 Hypoxia Diseases 0.000 description 3
- 108010074328 Interferon-gamma Proteins 0.000 description 3
- 108010002335 Interleukin-9 Proteins 0.000 description 3
- 108010028275 Leukocyte Elastase Proteins 0.000 description 3
- 102000016799 Leukocyte elastase Human genes 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 241000589970 Spirochaetales Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 206010069351 acute lung injury Diseases 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- XJUUDTMUUDAAPP-UHFFFAOYSA-N benzyl-[2-(2,6-dimethylanilino)-2-oxoethyl]-diethylazanium;hydroxide Chemical compound [OH-].C=1C=CC=CC=1C[N+](CC)(CC)CC(=O)NC1=C(C)C=CC=C1C XJUUDTMUUDAAPP-UHFFFAOYSA-N 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- 230000005750 disease progression Effects 0.000 description 3
- 238000005538 encapsulation Methods 0.000 description 3
- 235000019197 fats Nutrition 0.000 description 3
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 3
- TWSALRJGPBVBQU-PKQQPRCHSA-N glucagon-like peptide 2 Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O)[C@@H](C)CC)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=CC=C1 TWSALRJGPBVBQU-PKQQPRCHSA-N 0.000 description 3
- 108091005708 gustatory receptors Proteins 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 230000037353 metabolic pathway Effects 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 235000021391 short chain fatty acids Nutrition 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 3
- 239000011782 vitamin Substances 0.000 description 3
- 235000013343 vitamin Nutrition 0.000 description 3
- 229940088594 vitamin Drugs 0.000 description 3
- 229930003231 vitamin Natural products 0.000 description 3
- 235000019786 weight gain Nutrition 0.000 description 3
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 241000605059 Bacteroidetes Species 0.000 description 2
- 102100039398 C-X-C motif chemokine 2 Human genes 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- 206010065941 Central obesity Diseases 0.000 description 2
- 108010014414 Chemokine CXCL2 Proteins 0.000 description 2
- 102000016951 Chemokine CXCL2 Human genes 0.000 description 2
- 102000019034 Chemokines Human genes 0.000 description 2
- 108010012236 Chemokines Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000001528 Coronaviridae Infections Diseases 0.000 description 2
- 241000588722 Escherichia Species 0.000 description 2
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 2
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 2
- 101000858088 Homo sapiens C-X-C motif chemokine 10 Proteins 0.000 description 2
- 101000889128 Homo sapiens C-X-C motif chemokine 2 Proteins 0.000 description 2
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- 102000008070 Interferon-gamma Human genes 0.000 description 2
- 102000014158 Interleukin-12 Subunit p40 Human genes 0.000 description 2
- 108010011429 Interleukin-12 Subunit p40 Proteins 0.000 description 2
- 238000012313 Kruskal-Wallis test Methods 0.000 description 2
- 238000008214 LDL Cholesterol Methods 0.000 description 2
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 2
- 208000004852 Lung Injury Diseases 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 108010009474 Macrophage Inflammatory Proteins Proteins 0.000 description 2
- 102000009571 Macrophage Inflammatory Proteins Human genes 0.000 description 2
- 101710151805 Mitochondrial intermediate peptidase 1 Proteins 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 241000160321 Parabacteroides Species 0.000 description 2
- 229920003081 Povidone K 30 Polymers 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 206010062106 Respiratory tract infection viral Diseases 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- 206010069363 Traumatic lung injury Diseases 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000002891 anorexigenic effect Effects 0.000 description 2
- 235000019789 appetite Nutrition 0.000 description 2
- 230000036528 appetite Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000036996 cardiovascular health Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000002975 chemoattractant Substances 0.000 description 2
- 230000006020 chronic inflammation Effects 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 235000021316 daily nutritional intake Nutrition 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 230000000378 dietary effect Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 244000005709 gut microbiome Species 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 208000018875 hypoxemia Diseases 0.000 description 2
- 230000037451 immune surveillance Effects 0.000 description 2
- 239000012678 infectious agent Substances 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 239000003999 initiator Substances 0.000 description 2
- 210000004964 innate lymphoid cell Anatomy 0.000 description 2
- 229960003130 interferon gamma Drugs 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 229960004194 lidocaine Drugs 0.000 description 2
- 230000037356 lipid metabolism Effects 0.000 description 2
- 231100000515 lung injury Toxicity 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000000275 quality assurance Methods 0.000 description 2
- 231100000272 reduced body weight Toxicity 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- 230000003827 upregulation Effects 0.000 description 2
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 description 1
- KZDCMKVLEYCGQX-UDPGNSCCSA-N 2-(diethylamino)ethyl 4-aminobenzoate;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;hydrate Chemical compound O.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 KZDCMKVLEYCGQX-UDPGNSCCSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 102100036009 5'-AMP-activated protein kinase catalytic subunit alpha-2 Human genes 0.000 description 1
- 108091093088 Amplicon Proteins 0.000 description 1
- 108010072661 Angiotensin Amide Proteins 0.000 description 1
- 241000008921 Avian coronavirus Species 0.000 description 1
- 241000927512 Barnesiella Species 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 241001236205 Brenneria Species 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- 108700012434 CCL3 Proteins 0.000 description 1
- 101100346189 Caenorhabditis elegans mpc-1 gene Proteins 0.000 description 1
- 101100151946 Caenorhabditis elegans sars-1 gene Proteins 0.000 description 1
- 241001234029 Candidatus Soleaferrea Species 0.000 description 1
- 102000000013 Chemokine CCL3 Human genes 0.000 description 1
- 102000001326 Chemokine CCL4 Human genes 0.000 description 1
- 108010055165 Chemokine CCL4 Proteins 0.000 description 1
- 241000193403 Clostridium Species 0.000 description 1
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 206010011906 Death Diseases 0.000 description 1
- 241000500134 Dehalobacterium Species 0.000 description 1
- 206010060902 Diffuse alveolar damage Diseases 0.000 description 1
- 241001143779 Dorea Species 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 102000016942 Elastin Human genes 0.000 description 1
- 108010014258 Elastin Proteins 0.000 description 1
- 241000089032 Erysipelatoclostridium Species 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 241000711475 Feline infectious peritonitis virus Species 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 241000662772 Flavonifractor Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 101000783681 Homo sapiens 5'-AMP-activated protein kinase catalytic subunit alpha-2 Proteins 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010021113 Hypothermia Diseases 0.000 description 1
- 101150106931 IFNG gene Proteins 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- 238000012369 In process control Methods 0.000 description 1
- 241000711450 Infectious bronchitis virus Species 0.000 description 1
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 1
- 102000015271 Intercellular Adhesion Molecule-1 Human genes 0.000 description 1
- 102100037850 Interferon gamma Human genes 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 1
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- 241000125969 Lachnoclostridium Species 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 102100028123 Macrophage colony-stimulating factor 1 Human genes 0.000 description 1
- 101710127797 Macrophage colony-stimulating factor 1 Proteins 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 241000843248 Oscillibacter Species 0.000 description 1
- 241000266824 Oscillospira Species 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 206010035737 Pneumonia viral Diseases 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 108091008611 Protein Kinase B Proteins 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 208000029464 Pulmonary infiltrates Diseases 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 1
- 241000095588 Ruminococcaceae Species 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 241000123710 Sutterella Species 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 241000711484 Transmissible gastroenteritis virus Species 0.000 description 1
- 238000010162 Tukey test Methods 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 229940100228 acetyl coenzyme a Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000007963 carbohydrate restriction Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 229960004203 carnitine Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 1
- 239000005516 coenzyme A Substances 0.000 description 1
- 229940093530 coenzyme a Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 208000012696 congenital leptin deficiency Diseases 0.000 description 1
- 230000009351 contact transmission Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- PLCQGRYPOISRTQ-FCJDYXGNSA-L dexamethasone sodium phosphate Chemical compound [Na+].[Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COP([O-])([O-])=O)(O)[C@@]1(C)C[C@@H]2O PLCQGRYPOISRTQ-FCJDYXGNSA-L 0.000 description 1
- 229920003045 dextran sodium sulfate Polymers 0.000 description 1
- 230000003205 diastolic effect Effects 0.000 description 1
- 235000021196 dietary intervention Nutrition 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 230000005560 droplet transmission Effects 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 229920002549 elastin Polymers 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 235000021149 fatty food Nutrition 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 235000020803 food preference Nutrition 0.000 description 1
- 239000013022 formulation composition Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000003197 gene knockdown Methods 0.000 description 1
- 238000012252 genetic analysis Methods 0.000 description 1
- 230000005182 global health Effects 0.000 description 1
- 230000014101 glucose homeostasis Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 208000021760 high fever Diseases 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 229940048921 humira Drugs 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 230000002631 hypothermal effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 238000010965 in-process control Methods 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000022023 interleukin-5 production Effects 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 1
- 201000002364 leukopenia Diseases 0.000 description 1
- 231100001022 leukopenia Toxicity 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 231100000516 lung damage Toxicity 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000005399 mechanical ventilation Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- 208000001022 morbid obesity Diseases 0.000 description 1
- 230000001459 mortal effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 235000020956 nicotinamide riboside Nutrition 0.000 description 1
- 239000011618 nicotinamide riboside Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 201000007407 panuveitis Diseases 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 210000003024 peritoneal macrophage Anatomy 0.000 description 1
- 210000004303 peritoneum Anatomy 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 208000019764 polyarticular juvenile idiopathic arthritis Diseases 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 238000012175 pyrosequencing Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000012429 release testing Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000011506 response to oxidative stress Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000036186 satiety Effects 0.000 description 1
- 235000019627 satiety Nutrition 0.000 description 1
- 235000021003 saturated fats Nutrition 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000009919 sequestration Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- CWERGRDVMFNCDR-UHFFFAOYSA-M thioglycolate(1-) Chemical compound [O-]C(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-M 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 230000006433 tumor necrosis factor production Effects 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 244000052613 viral pathogen Species 0.000 description 1
- 208000009421 viral pneumonia Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present disclosure provides a method for treatment, prevention, and/or slowing of progression for various chronic inflammatory disorder groups including (1) type 2 diabetes group (metabolic syndrome (MET), obesity, hyperglycemia); (2) ARDS (acute respiratory distress syndrome); (3) chronic autoimmune inflammatory disorders (rheumatoid arthritis (RA), lupus, and psoriasis); (4) inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis; (5) metabolome-mediated diseases (atherosclerosis, hypertension, and congestive heart failure); and (6) hyperphagia disorders such as Prader-Willi Syndrome and other monogenic and syndromic obesity disorders including leptin pathway deficiencies, each comprising administering orally a pharmaceutical composition comprising a denatonium salt.
- MET type 2 diabetes group
- ARDS acute respiratory distress syndrome
- RA chronic autoimmune inflammatory disorders
- IBD inflammatory bowel diseases
- metabolome-mediated diseases atherosclerosis, hypertension, and congestive
- the present disclosure is based on readouts from a series of studies tracking clusters of biomarkers levels to track mediators of inflammatory disorders and mediators of gut-signaling hormones in response to orally administered denatonium salts.
- the present disclosure further provides a pharmaceutical composition for treatment and prevention of various inflammatory conditions that can be tracked by pro-inflammatory biomarkers, comprising administering a pharmaceutical composition comprising a denatonium salt.
- the pharmaceutical composition for daily oral administration comprises a denatonium salt delivering a daily total dose of from about 20 mg to about 5000 mg to a human adult BID.
- the denatonium salt is selected from the group consisting of denatonium acetate, denatonium citrate, denatonium maleate and denatonium tartrate.
- TNF tumor necrosis factor
- IL interleukin
- TNF tumor necrosis factor
- IL interleukin
- Such therapeutic proteins are approved for rheumatoid arthritis, polyarticular juvenile idiopathic arthritis (JIA) in children, psoriatic arthritis, lupus, ankylosing spondylitis (AS), chronic plaque psoriasis (Ps), panuveitis, IBD including ulcerative colitis and Crohn's disease, and many other diseases.
- JIA polyarticular juvenile idiopathic arthritis
- AS ankylosing spondylitis
- Ps chronic plaque psoriasis
- panuveitis IBD including ulcerative colitis and Crohn's disease, and many other diseases.
- These biological drugs act by binding and mopping up circulating TNF ⁇ (and IL-6) with an antibody or a fusion protein such as etanercept)(Embrel®.
- these anti-TNF ⁇ drugs and other biological drugs that indiscriminately bind and mop up inflammatory cytokines have severe side effects.
- the side effects are caused by inhibition of the vast majority of TNF signaling.
- TNF has an immune surveillance function (that is also inhibited by these biological drugs)
- there is greater susceptibility to infection and decreased immune surveillance including increased incidence of various infectious diseases and malignancies including leukemias and lymphomas listed on black box warning labels. Therefore, there is a need in the art for more cost-effective small molecule therapeutics that knock down (but not necessarily eliminate) circulating TNF.
- adalimumab (Humira®) on the U.S. FDA approved label indicates the following side effects of increased risk for serious infections (i.e., including TB and infections caused by viruses, fungi, or bacteria), exacerbation of hepatitis B infection in carriers of the virus, allergic reactions, and various leukemias and lymphomas.
- Metabolic syndrome is a multiplex of factors increasing the risk of the development of type 2 diabetes and cardiovascular disease.
- METS is a clustering of at least three of the five following medical conditions: (1) visceral obesity; (2) elevated blood pressure; (3) increased blood sugar; (4) high serum triglycerides; and (5) low serum high density lipoprotein (HDL).
- metabolic syndrome presents with central obesity and any two of the following: (1) raised triglycerides (TG) of >150 mg/dL (1.7 mmol/L), or specific treatment for increased triglycerides; (2) reduced HDL of ⁇ 40 mg/dL (1.03 mmol/L) in males ⁇ 50 mg/dL (1.29 mmol/L in females; (3) raised blood pressure (BP) with systolic>130 or diastolic>85 mm Hg or treatment for hypertension and (4) raised fasting plasma glucose (FPG)>100 mg/dL (5.6 mmol/L) or previous diagnosis of type 2 diabetes.
- TG raised triglycerides
- BP blood pressure
- FPG fasting plasma glucose
- Metabolic syndrome may also be defined as presentation of hyperinsulinemia and any two of the following: (1) abdominal obesity (waist/hip ration>0.90 or BMI 30 kg/m 2 ), (2) dyslipidemia (TG>1.7 or HDL ⁇ 0.9 mmol/L) and (3) hypertension (BP>140/90 mm Hg or use of antihypertensive medication).
- abdominal obesity Waist/hip ration>0.90 or BMI 30 kg/m 2
- dyslipidemia TG>1.7 or HDL ⁇ 0.9 mmol/L
- hypertension BP>140/90 mm Hg or use of antihypertensive medication.
- TNF ⁇ inflammatory biomarkers
- IL-6 interleukin-6
- MCP-1 from fasting participants
- METS affects 20-25% of the global adult population, including 35% of the U.S. adult population.
- METS is present in about 60% of U.S. residents aged>50.
- METS correlates with a higher frequency of autoimmune diseases. Therefore, there is a need in the art to provide safer and effective METS therapeutics.
- ARDS Acute respiratory distress syndrome
- ARDS is a life-threatening disease, characterized by acute onset of hypoxia and pulmonary infiltrates, and incited by conditions such as sepsis, pneumonia, trauma, burns, pancreatitis and blood transfusion.
- ARDS causes diffuse lung inflammation which leads to increased pulmonary vascular permeability, pulmonary edema, and alveolar epithelial injury.
- the diagnosis of ARDS is made based on the following criteria: (1) acute onset; (2) bilateral lung infiltrates of a non-cardiac origin on chest x-ray or tomographic (CT) scan; and (3) moderate to severe impairment of oxygenation.
- Severe ARDS carries a mortality rate of 45%.
- ARDS The severity of the ARDS is defined by the degree of hypoxemia, which is calculated as the ratio of arterial oxygen tension to fraction of inspired oxygen (PaO 2 /FiO 2 ).
- ARDS can be mild, moderate or severe as clarified by the Berlin definition of ARDS, wherein PaO 2 /FiO 2 is 200-300 for mild, 100-199 for moderate and ⁇ 100 for severe.
- ARDS In general, the development of ARDS can be separated into two phases: an initiator stage followed by an effector stage.
- the initiator phase of ARDS involves the release of inflammatory mediators (i.e., cytokines; complement and coagulation factors; and arachidonic acid metabolites) which promote systemic inflammation resulting in pulmonary neutrophil sequestration.
- the second stage, the effector phase involves the activation of neutrophils with subsequent release of toxic oxygen radicals and proteolytic enzymes, specifically neutrophil elastase (NE).
- NE neutrophil elastase
- NE has the capacity to injure pulmonary endothelial cells and degrade products of the extracellular matrix, such as elastin, collagen, and fibronectin which comprise the lung basement membrane.
- ARDS Many diverse forms of ARDS exist with disparate etiologies and courses, although the end-state pathologies of these diverse forms are the same. Examples of clinical events that may precipitate different forms of ARDS include trauma, hemorrhage, diffuse pneumonia, virally induced pneumonia (including, but not limited to COVID-19 and SARS), inhalation of toxic gases, and sepsis. In the case of the 2020 COVID-19 pandemic, it is a viral pneumonia that drives the ARDS observed in many patients requiring critical care. Irrespective of initial cause, ARDS has the following in common: intrapulmonary fluid accumulation and exudates leading to diffuse alveolar damage and impaired gas exchange in the alveoli. What is common (irrespective of the initial cause of the ARDS) downstream is a worsening due to inflammation, fluid release, cell migration and proliferation as well as increases of proinflammatory cytokines.
- Viral respiratory infection is generally characterized by an incubation period typically 2-7 days in length, with infected individuals typically exhibiting high fevers, sometimes with accompanying chills, headache, malaise and myalgia.
- Viral infection of the lungs accounts for approximately 10-15% of ICU admissions in the US per year without a pandemic and is responsible for a significant percentage of deaths from influenza each year without a coronavirus pandemic.
- the 2020 pandemic from COVID-19 illustrates this course of disease progression. The illness progresses with the onset of a dry, non-productive cough or dyspnea, accompanied by or advancing into hypoxemia. A significant number of cases require intubation and mechanical ventilation. Furthermore, at the peak of respiratory illness, approximately 50% of infected individuals develop leukopenia and thrombocytopenia ( MMWR Morb Mortal Wkly Rep. 2003 Mar. 28; 52(12):255-6).
- SARS-associated coronavirus SARS-CoV
- coronavirus SARS-associated coronavirus
- Coronaviruses are generally characterized as single-stranded RNA viruses having genomes of approximately 30,000 nucleotides ( Science. 2003 May 30; 300(5624):1394-9).
- Coronaviruses fall into three known groups; the first two groups cause mammalian coronavirus infections, and the third group causes avian coronavirus infections (J. S. M. Peiris, in Medical Microbiology (Eighteenth Edition), 2012, 587-593). Coronaviruses are believed to be the causative agents of several severe diseases in many animals, for example, infectious bronchitis virus, feline infectious peritonitis virus and transmissible gastroenteritis virus, are significant veterinary pathogens (Viruses. 2019 January; 11(1): 59).
- the present invention provides a method for slowing down atherosclerotic changes in vascular cells by reducing gut signals that support atherosclerotic changes in vascular cells.
- the modulation of food behavior can provide a mechanism for the prevention of the development of metabolic disorders including cardiovascular diseases (Langley-Evans et al., Matern Child Nutr., 1, 142-148, 2005), particularly when food with a high caloric density or rich in fat, particularly saturated fat, is widely available, as happens in our developed societies.
- leptin a circulating protein codified by the ob gene which is mainly expressed in the adipose tissue.
- Leptin plays a central role in the regulation of energy balance, inhibiting food intake and increasing energy waste (Zhang et al., Nature, 372, 425-432, 1994).
- This protein circulates in blood in a concentration that is proportional to the size of the fat depots; it passes through the blood-brain barrier by means of a saturable system and exerts most of its effects on energy balance at a central level, through the interaction of the protein with receptors located in hypothalamic neurons and in other regions of the brain (Tartaglia et al., Cell. 83, 1263-1271, 1995).
- leptin in the treatment or prevention of diabetes mellitus (WO97/02004) whose direct cause is obesity was proposed. Although it was thought that the short-term anorexigenic role of leptin could contribute to controlling the problem of obesity and related disorders in obese people, unfortunately, leptin administration alone has been ineffective as a practical treatment, in part due to tolerance as well as compensatory upregulation of other pathways mediating hunger and satiety. Long term treatment outcome has remained unsatisfactory.
- leptin resistance would be the main determinant of body weight increase and age-related adiposity [Iossa et al., J. Nutr., 1999, 129, 1593-6].
- concentration of circulating leptin is usually considered to be proportional to body fat mass and this mass usually increases as we grow old, there is evidence that the increase in leptinemia and the development of leptin resistance with age occurs, at least in part, independently of the increase in adiposity (Gabriely et al., Diabetes, 2002, 51, 1016-21).
- the present disclosure provides a method for treatment, prevention, and/or slowing of progression for various chronic inflammatory disorder groups including (1) type 2 diabetes group (metabolic syndrome (MET), obesity, hyperglycemia); (2) ARDS (acute respiratory distress syndrome); (3) chronic autoimmune inflammatory disorders (rheumatoid arthritis (RA), lupus, and psoriasis); (4) inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis; (5) metabolome-mediated diseases (atherosclerosis, hypertension, and congestive heart failure); and (6) hyperphagia disorders such as Prader-Willi Syndrome and other monogenic and syndromic obesity disorders including leptin pathway deficiencies, each comprising administering orally a pharmaceutical composition comprising a denatonium salt.
- MET type 2 diabetes group
- ARDS acute respiratory distress syndrome
- RA chronic autoimmune inflammatory disorders
- IBD inflammatory bowel diseases
- metabolome-mediated diseases atherosclerosis, hypertension, and congestive
- the present disclosure is based on readouts from a series of studies tracking clusters of biomarkers levels to track mediators of inflammatory disorders and mediators of gut-signaling hormones in response to orally administered denatonium salts.
- the present disclosure further provides a pharmaceutical composition for treatment and prevention of various inflammatory conditions that can be tracked by pro-inflammatory biomarkers, comprising administering a pharmaceutical composition comprising a denatonium salt.
- the pharmaceutical composition for daily oral administration comprises a denatonium salt delivering a daily total dose of from about 20 mg to about 5000 mg to a human adult BID.
- the denatonium salt is selected from the group consisting of denatonium acetate, denatonium citrate, denatonium maleate and denatonium tartrate.
- the present disclosure provides a method for treatment, prevention and slowing down exacerbation of type 2 diabetes including metabolic syndrome (MET), obesity, and hyperglycemia, comprising administering orally a pharmaceutic composition comprising a denatonium salt, wherein the denatonium salt is selected from the group consisting of denatonium acetate (DA), denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate.
- the pharmaceutical composition further comprises from about 0.5 g to about 5 g acetic acid. More preferably, the dosage per day of the acetic acid for an adult is from about 1.5 g to about 3 g.
- the daily dosage of the denatonium salt for an adult is from about 20 mg to about 5000 mg or from about 5 mg/kg to about 150 mg/kg body weight per day. More preferably, the daily dosage of DA for an adult is from about 50 mg to about 1000 mg. Most preferably, the daily dosage of DA for an adult is from about 60 mg to about 500 mg, or to achieve a concentration in the GI tract of from about 10 parts per billion to about 50 ppm.
- the daily dose of the denatonium salt is administered once per day, twice per day or three times per day.
- the present disclosure provides a method for treatment, prevention and slowing down exacerbation of acute pulmonary inflammatory disorders including ARDS, comprising administering orally a pharmaceutic composition comprising a denatonium salt, wherein the denatonium salt is selected from the group consisting of denatonium acetate (DA), denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate.
- the pharmaceutical composition further comprises from about 0.5 g to about 5 g acetic acid. More preferably, the dosage per day of the acetic acid for an adult is from about 1.5 g to about 3 g.
- the daily dosage of the denatonium salt for an adult is from about 20 mg to about 5000 mg or from about 5 mg/kg to about 150 mg/kg body weight per day. More preferably, the daily dosage of DA for an adult is from about 50 mg to about 1000 mg. Most preferably, the daily dosage of DA for an adult is from about 60 mg to about 500 mg, or to achieve a concentration in the GI tract of from about 10 parts per billion to about 50 ppm.
- the daily dose of the denatonium salt is administered once per day, twice per day or three times per day.
- the present disclosure provides a method for treatment, prevention and slowing down exacerbation of chronic autoimmune inflammatory disorders group of indications selected from the group consisting of rheumatoid arthritis (RA), lupus, and psoriasis, comprising administering orally a pharmaceutic composition comprising a denatonium salt, wherein the denatonium salt is selected from the group consisting of denatonium acetate (DA), denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate.
- the pharmaceutical composition further comprises from about 0.5 g to about 5 g acetic acid.
- the dosage per day of the acetic acid for an adult is from about 1.5 g to about 3 g.
- the daily dosage of the denatonium salt for an adult is from about 20 mg to about 5000 mg or from about 5 mg/kg to about 150 mg/kg body weight per day.
- the daily dosage of DA for an adult is from about 50 mg to about 1000 mg.
- the daily dosage of DA for an adult is from about 60 mg to about 500 mg, or to achieve a concentration in the GI tract of from about 10 parts per billion to about 50 ppm.
- the daily dose of the denatonium salt is administered once per day, twice per day or three times per day.
- the present disclosure provides a method for treatment, prevention and slowing down exacerbation of chronic IBD group of indications selected from the group consisting of Crohn's Disease, and ulcerative colitis, comprising administering orally a pharmaceutic composition comprising a denatonium salt, wherein the denatonium salt is selected from the group consisting of denatonium acetate (DA), denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate.
- the pharmaceutical composition further comprises from about 0.5 g to about 5 g acetic acid. More preferably, the dosage per day of the acetic acid for an adult is from about 1.5 g to about 3 g.
- the daily dosage of the denatonium salt for an adult is from about 20 mg to about 5000 mg or from about 5 mg/kg to about 150 mg/kg body weight per day. More preferably, the daily dosage of DA for an adult is from about 50 mg to about 1000 mg. Most preferably, the daily dosage of DA for an adult is from about 60 mg to about 500 mg, or to achieve a concentration in the GI tract of from about 10 parts per billion to about 50 ppm.
- the daily dose of the denatonium salt is administered once per day, twice per day or three times per day.
- the present disclosure provides a method for treatment, prevention and slowing down exacerbation of metabolome mediated group of indications selected from the group consisting of atherosclerosis, hypertension, and congestive heart failure (CHF), comprising administering orally a pharmaceutic composition comprising a denatonium salt, wherein the denatonium salt is selected from the group consisting of denatonium acetate (DA), denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate.
- the pharmaceutical composition further comprises from about 0.5 g to about 5 g acetic acid. More preferably, the dosage per day of the acetic acid for an adult is from about 1.5 g to about 3 g.
- the daily dosage of the denatonium salt for an adult is from about 20 mg to about 5000 mg or from about 5 mg/kg to about 150 mg/kg body weight per day. More preferably, the daily dosage of DA for an adult is from about 50 mg to about 1000 mg. Most preferably, the daily dosage of DA for an adult is from about 60 mg to about 500 mg, or to achieve a concentration in the GI tract of from about 10 parts per billion to about 50 ppm.
- the daily dose of the denatonium salt is administered once per day, twice per day or three times per day.
- the present disclosure provides a method for treatment, or slowing down exacerbation of a hyperphagia group of indications selected from the group consisting of Prader-Willi Syndrome and leptin pathway deficiencies, comprising administering orally a pharmaceutic composition comprising a denatonium salt, wherein the denatonium salt is selected from the group consisting of denatonium acetate (DA), denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate.
- the pharmaceutical composition further comprises from about 0.5 g to about 5 g acetic acid. More preferably, the dosage per day of the acetic acid for an adult is from about 1.5 g to about 3 g.
- the daily dosage of the denatonium salt for an adult is from about 20 mg to about 5000 mg or from about 5 mg/kg to about 150 mg/kg body weight per day. More preferably, the daily dosage of DA for an adult is from about 50 mg to about 1000 mg. Most preferably, the daily dosage of DA for an adult is from about 60 mg to about 500 mg, or to achieve a concentration in the GI tract of from about 10 parts per billion to about 50 ppm.
- the daily dose of the denatonium salt is administered once per day, twice per day or three times per day.
- FIG. 1 shows body weight over time with administration of DA compared to vehicle control.
- FIG. 2 shows body weight change over time with administration of DA compared to vehicle control.
- FIG. 3 shows the body weight change at day 28. There was no statistically significant difference in body weight change at Day 28 between the two experimental groups.
- FIG. 4 shows fasting blood glucose levels at day 28. There was no statistically significant difference in blood fasting glucose level at Day 28 between the two experimental groups.
- FIG. 5 shows HbA1c levels at day 28. There was no statistically significant difference in blood HbA1c levels at Day 28 between the two experimental groups.
- FIG. 6 shows blood HDL levels at day 28. Animals treated with DA at 23.1 mg/kg showed a statistically significant decrease in blood HDL level at Day 28 compared to vehicle-treated animals.
- FIG. 7 shows blood LDL cholesterol levels at day 28. There was no statistically significant difference in blood LDL levels at Day 28 between the two experimental groups.
- FIG. 8 shows blood total cholesterol level (LDL plus HDL) at day 28. Animals treated with DA at 23.1 mg/kg showed an almost significant decrease in blood total cholesterol levels at Day 28 compared to vehicle-treated animals.
- FIG. 9 shows blood insulin levels at day 28. There was no statistically significant difference in blood insulin levels at Day 28 between the two experimental groups.
- FIG. 10 shows blood bile acid levels at day 28. There was no statistically significant difference in blood bile acid levels at Day 28 between the two experimental groups.
- FIG. 11 shows granulocyte number and percentage at pre-dose and at day 28, Although there was no statistically significant difference, DA-treated animals showed a trend of increasing change in granulocyte number as compared to vehicle-treated controls.
- FIG. 12 shows monocyte number and percentage at pre-dose and at day 28. Although there was no statistically significant difference, DA-treated animals showed a trend of increasing change in monocyte number and percentage as compared to vehicle-treated controls.
- FIG. 13 shows changes in lymphocyte and white blood cell number at pre-dose and at day 28. Although there was no statistically significant difference, DA-treated animals showed a trend of increasing change in lymphocyte and white blood cell numbers and percentage as compared to vehicle-treated controls.
- FIG. 14 shows cumulative food consumption over 28 days. There was no statistically significant difference in food consumption over 28 days between the two experimental groups.
- FIG. 15 shows various cytokines analysis in blood at day 28.
- KC cytokine-induced neutrophil chemoattractant (CXCL1); MCP-1: monocyte chemoattractant protein-1; MIP-1: macrophage inflammatory protein 1; M-CSF, macrophage colony-stimulating factor; MIP-2: macrophage inflammatory protein 2 (CXCL2); VEGF: vascular endothelial growth factor.
- CXCL1 and M-CSF showed significant decreases with DA administration.
- FIG. 16 shows various cytokines analysis in blood at day 28.
- IP-10 IFN- ⁇ -Inducible Protein 10 (CXCL10).
- IL-10 and IL-12 showed significant decreases with DA administration.
- FIG. 17 shows various cytokines analysis in blood at day 28.
- G-CSF granulocyte colony-stimulating factor
- GM-CSF granulocyte-macrophage colony-stimulating factor
- IFN ⁇ interferon gamma
- IL-1 ⁇ , IL-1 ⁇ , IL-2 and IL-5 GM-CSF, IFN ⁇ , and IL-5 showed significant decreases with DA administration.
- FIG. 18 shows a figure of infiltrating cell counts in air pouch exudates wherein pre-treatment with DA decreased infiltrating cell counts in air pouch exudates following LPS induction in a dose-dependent manner.
- Animals were pre-treated with DA at 96.4 mg/kg showed significantly lower infiltrating cell count as compared with those pre-treated with vehicle and the lower dose of DA between the results.
- FIG. 19 shows a figure of IL-6 levels in air pouch exudates wherein pre-treatment with DA decreased infiltrating cell counts in air pouch exudates following LPS induction in a dose-dependent manner.
- Animals were pre-treated with DA at 96.4 mg/kg showed significantly lower IL-6 levels as compared with those pre-treated with vehicle and the lower dose of DA between the results.
- FIGS. 20 - 27 show the cytokines levels for G-CSF, Eotaxin, GM-CSF, IFN ⁇ , IL-1a, IL-1b, IL-2, and IL-3, respectively.
- IL-1b showed significant reduction with the higher dose of DA.
- FIGS. 28 - 35 show the cytokines levels for IL-4, IL-5, IL-7, IL-9, IL-10, IL-12p40, IL-12p70, and IL-13, respectively.
- IL-10 showed significant reduction with the higher dose of DA.
- FIGS. 36 - 43 show the cytokines levels for IL-15, IL-17, LIF, LIX, IP-10, KC. MCP-1, and MCP-1a, respectively.
- IL-17 showed significant reduction with the higher dose of DA.
- FIGS. 44 - 50 show the cytokines levels for MIP-1b, MIP-2, M-CSF, MIG, RANTES, VEGF, and TNF-1a, respectively.
- TNF-1a showed significant reduction with the higher dose of DA.
- FIG. 51 shows a summary for the higher dose (orange) and the lower dose (blue) showing significance with an asterisk.
- FIG. 53 shows body weight at day 10. Animals treated with 69.3 mg/kg DA, BID showed significant effect against DSS-induced body weight loss, as compared to vehicle.
- FIG. 54 shows fecal occult blood scores during the study period. Treatment with DA showed a significant main effect on fecal blood status.
- FIG. 55 shows fecal consistency score during the study period. Treatment with DA showed significant main effect on fecal consistency.
- FIG. 56 shows the combined fecal score during the study period. Treatment with DA showed a significant main effect on combined fecal status.
- FIGS. 57 and 58 shows colon weight and length at day 10, respectively. Although no significant difference was observed, treatment with high-dose of DA could counteract DSS-induced decrease in colon weight and length in mice.
- FIG. 59 shows spleen weight at day 10. Although no significant effect was observed, treatment with high-dose of DA showed a trend to counteract DSS-induced spleen weight loss in mice.
- FIG. 60 shows changes a phylum levels wherein week 4 showed>95% confidence changes in the microbiome at the phylum level for the following: Treatment increased proteobacteria*, verrucomicrobia*, cyanobacteria*. Treatment decreased Bacteroidetes, firmicutes*, deferribacteres and spirochetes*. (*significant differences from control or time 0).
- FIG. 61 shows significant differences for treatment versus control at a family level.
- FIG. 62 shows a principal coordinate analysis plot.
- FIG. 63 A-B show a significant enrichment in the pathways for biosynthesis of unsaturated fatty acids upon 4-week DA treatment (upper panel: individual data; lower panel: group data).
- FIG. 64 A-B show a significant enrichment in the pathways for metabolism of arachidonic acid upon 4-week DA treatment (upper panel: individual data; lower panel: group data).
- FIG. 65 A-B show a significant enrichment in the pathways for metabolism of cofactors and vitamins upon 4-week DA treatment (upper panel: individual data; lower panel: group data).
- FIG. 66 A-B show a significant enrichment in pathways for lysine degradation upon 4-week DA treatment (upper panel: individual data; lower panel: group data).
- FIG. 67 shows a significant enrichment in pathways for glycolysis and gluconeogenesis upon 4-week DA treatment (group data).
- FIG. 68 shows a significant enrichment in phosphatidylinositol signaling upon 4-week DA treatment (group data).
- FIG. 69 A-B show a significantly decreased signaling for arginine and ornithine metabolism upon 4-week DA treatment (upper panel: individual data; lower panel: group data).
- FIGS. 70 A-C show graphs comparing biomarkers across many studies by family, showing decreased mean percentages.
- FIG. 71 it should be noted that clusters of multiple biomarkers predict effectiveness for each disease indication and that grouping is shown in FIG. 71 .
- FIGS. 72 and 73 shows cytokine profiles in lung lavage fluids from the data in Examples 7 and 8, respectively.
- FIG. 74 shows DA treatment significantly reduced body weight gain at day 57 in DIO mice as compared to vehicle and CQL.
- FIG. 75 A shows that at Day 14, treatment with DA significantly reduced daily food intake in DIO mice as compared to vehicle.
- FIG. 75 B shows that treatment with DA significantly increased daily water intake at Day 28, while treatment with CQL significantly decreased daily water intake, as compared to vehicle, both from Example 9.
- FIG. 76 shows that treatments with DA and CQL significantly reduced serum HbA1c level at Day 28, but considerably increased the HbA1c level at Day 56 in DIO mice.
- FIG. 77 shows that treatments with DA significantly reduced serum insulin level at Day 28 as compared to vehicle control in DIO mice.
- FIG. 79 shows that treatments with DA significantly increased serum GLP-1 levels in DIO mice at Days 7 and 56 as compared to vehicle control.
- FIG. 80 shows that treatments with DA significantly increased serum GLP-2 levels in DIO mice at Day 56 as compared to vehicle control.
- FIG. 81 shows that treatments with DA significantly increased serum CCK levels in DIO mice at Day 56 as compared to vehicle control.
- FIG. 82 shows that treatments with DA significantly increased serum PYY levels in DIO mice at Day 56 as compared to vehicle control.
- FIG. 83 shows treatment with DA significantly decreased serum glucose levels in ob/ob mice.
- FIG. 84 shows that treatments with DA significantly lowered serum triglyceride levels as compared to vehicle control in ob/ob mice.
- FIG. 85 shows that treatments with DA significantly increased serum bile acids levels as compared to vehicle control in ob/ob mice.
- FIG. 86 shows that treatments with DA significantly lowered serum LDL levels as compared to vehicle control in ob/ob mice.
- the present disclosure provides a method for treatment, prevention, and/or slowing of progression for various chronic inflammatory disorder groups including (1) type 2 diabetes group (metabolic syndrome (MET), obesity, hyperglycemia); (2) ARDS (acute respiratory distress syndrome); (3) chronic autoimmune inflammatory disorders (rheumatoid arthritis (RA), lupus, and psoriasis); (4) inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis; (5) metabolome-mediated diseases (atherosclerosis, hypertension, and congestive heart failure); and (6) hyperphagia disorders such as Prader-Willi Syndrome and other monogenic and syndromic obesity disorders including leptin pathway deficiencies, each comprising administering orally a pharmaceutical composition comprising a denatonium salt.
- MET type 2 diabetes group
- ARDS acute respiratory distress syndrome
- RA chronic autoimmune inflammatory disorders
- IBD inflammatory bowel diseases
- metabolome-mediated diseases atherosclerosis, hypertension, and congestive
- the present disclosure is based on readouts from a series of studies tracking clusters of biomarkers levels to track mediators of inflammatory disorders and mediators of gut-signaling hormones in response to orally administered denatonium salts.
- the present disclosure further provides a pharmaceutical composition for treatment and prevention of various inflammatory conditions that can be tracked by pro-inflammatory biomarkers, comprising administering a pharmaceutical composition comprising a denatonium salt.
- the pharmaceutical composition for daily oral administration comprises a denatonium salt delivering a daily total dose of from about 20 mg to about 5000 mg to a human adult BID.
- the denatonium salt is selected from the group consisting of denatonium acetate, denatonium citrate, denatonium maleate and denatonium tartrate.
- the present disclosure is based on a discovery of (1) a cluster of surprising results from what started as a weight loss in vivo study in a predictive ob/ob obesity mouse model with a denatonium salt and placebo controls.
- the data from several studies in various in vivo models showed that orally administered denatonium salt with an organic acid anion show treatment efficacy and showed significant anti-inflammatory effects first by measuring inflammatory cytokines in the blood and other fluids (e.g., air pouch exudates and lung lavage fluids) as biomarkers and then gut signaling peptides.
- the methods of treatment that oral administration provided data showing efficacy for methods of treatment, prevention and slowing down disease progression in indications including metabolic syndrome (METS), obesity (inflammatory mediated), ARDS, rheumatoid arthritis (RA), lupus, and psoriasis (Examples 1 and 2); (2) an in vivo study in a dextran sulfate sodium (DSS)-induced colitis in a mouse model showing treatment and prevention efficacy in indications including inflammatory bowel diseases (IBD), mainly comprising ulcerative colitis and Crohn's disease (Example 3); and (3) a four week microbiome study in mice fed a high fat diet showing treatment and prevention efficacy for atherosclerosis, hypertension, and congestive heart failure (Example 4 and below).
- a cluster of proinflammation-indicating cytokines measured achieved significant differences between drug administered mice and control mice. Weight loss showed strong trends to in vivo efficacy with DA administration but was not similarly statistically
- the cytokine data provided herein show in the inflammatory bowel disease model (Example 3), and in an air pouch model for inflammatory diseases, that the study drug, DA, did exhibit therapeutic activity in three areas: (1) to treat or prevent METS, (2) to treat or prevent general inflammatory diseases including autoimmune diseases; (3) to treat inflammatory bowel diseases including Crohn's Disease and ulcerative colitis; and (4) to treat cardiovascular diseases such as atherosclerosis, hypertension and congestive heart failure from microbiome data.
- a denatonium salt pharmaceutical composition shows safety and efficacy to (1) treat or prevent METS; (2) treat obesity and effect weight loss; (3) treat autoimmune inflammatory conditions rheumatoid arthritis (RA) lupus, and psoriasis; (4), treat Crohn's Disease and inflammatory bowel disease (IBD); and (5) treat or slow disease progression for cardiovascular diseases of atherosclerosis, hypertension and congestive heart failure.
- the denatonium salt is selected from the group consisting of denatonium acetate, denatonium citrate, denatonium maleate and denatonium tartrate. More preferably, the denatonium salt for treating the foregoing listed indication is administered orally from about 25 mg to about 500 mg per day to an adult BID.
- Example 2 study provided surprising results of statistical significance in reducing IL-5 production, which indicates the effectiveness of the present pharmaceutical composition of denatonium salts including DA in treating ARDS.
- This example describes the synthesis of denatonium acetate (DA).
- a reflux apparatus add 25 g of lidocaine, 60 ml of water and 17.5 g of benzyl chloride with stirring and heating in 70-90° C.
- the solution needs to be heated and stirred in the before given value for 24 h, the solution needs to be cooled down to 30° C.
- the unreacted reagents are removed with 3 ⁇ 10 mL of toluene.
- stirring dissolve 65 g of sodium hydroxide into 65 mL of cold water and add it to the aqueous solution with stirring over the course of 3 h. Filter the mixture, wash with some water and dry in open air. Recrystallize in hot chloroform or hot ethanol.
- This provides an immediate release 50 mg granule formulation of denatonium acetate monohydrate (DA) as a free base as an immediate gastric release oral pharmaceutical formulation.
- DA denatonium acetate monohydrate
- Table 1 shows qualitative and quantitative formulation composition of DA.
- Drug layering process was performed in a Fluid bed granulator equipped with the rotor insert (rotor granulator).
- Drug solution was prepared by solubilizing Povidone K30 (Kollidon 30) and Denatonium Acetate in ethyl alcohol. The drug solution was sprayed tangentially on to the bed of sugar spheres (35/45 mesh) moving in a circular motion in the rotor granulator. The final drug loaded pellets were then dried for ten (10) minutes in the rotor granulator, discharged and screened through a #20 mesh.
- Seal coating dispersion was prepared by separately dissolving Hypromellose E5 in a mixture (1:1) of ethyl alcohol and purified water until a clear solution was obtained. The remaining quantity of ethyl alcohol was then added to the above solution followed by talc. The dispersion was mixed for 20 minutes to allow for uniform dispersion of talc. The seal coating dispersion was sprayed tangentially on to the drug loaded pellets to achieve 5% weight gain. The seal coated pellets were then dried for five (5) minutes in the rotor granulator, discharged and dried further in a tray dryer/oven at 55° C. for 2 hours. The seal coated pellets were then screened through a #20 mesh.
- the seal coated pellets were blended with talc screened through mesh #60 using a V-Blender for ten (10) minutes and discharged.
- the blended seal coated beads, Denatonium IR Pellets, were used for encapsulation.
- the Denatonium IR pellets 50 mg, were filled into size 1, white opaque hard gelatin capsules using an auto capsule filling machine. Capsules were then passed through an in-line capsule polisher and metal detector. In-process controls for capsule weight and appearance was performed during the encapsulation process. Acceptable quality limit (AQL) sampling and testing was performed by Quality Assurance (QA) on a composite sample during the encapsulation process. Finished product composite sample was collected and analyzed as per specification for release testing.
- AQL Quality Assurance
- Packaging Capsules, 50 mg-30 Counts
- the 50 mg capsules were packaged in 30 counts into 50/60 cc White HDPE round S-line bottles with 33 mm White CRC Caps. The bottles were torqued and sealed using an induction sealer.
- FIGS. 70 A-C show graphs comparing biomarkers across many studies. Table 2 groups the biomarkers by family, shows decreased mean percentages and shows which disease indications are impacted and predicted by each biomarker. It should be noted that clusters of multiple biomarkers predict effectiveness for each disease indication and that grouping is shown in FIG. 71 .
- Arachidonic acid metabolites are important factors in the initiation and resolution of inflammation, and have been linked to the pathophysiology of obesity, diabetes mellitus, nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), and cardiovascular diseases ( Int. J. Mol. Sci. 2018; 19(11): 3285).
- NAFLD nonalcoholic fatty liver disease
- NASH nonalcoholic steatohepatitis
- cardiovascular diseases Int. J. Mol. Sci. 2018; 19(11): 3285).
- Cofactors including 1-carnitine, nicotinamide riboside (NR), 1-serine, and N-acetyl-1-cysteine (NAC), have been demonstrated in human clinical studies to improve altered biological functions associated with different human diseases ( Nutrients. 2019; 11(7):1578).
- Multiple vitamins and their derivatives have therapeutic potential for prevention and treatment of metabolic syndrome diseases, including diabetes mellitus ( Can. J. Physiol. Pharmacol. 2015; 93(5):355-62 ; Endocr. Metab. Immune Disord. Drug Targets. 2015; 15(1):54-63).
- SCFA Short chain fatty acid
- phosphatidylinositol signaling There was a significant phosphatidylinositol pathway upregulation. It has been documented that phosphatidylinositol pathways (e.g., PI3K/AKT, MAPK and AMPK pathways) are essential for glucose homeostasis. Moreover, deregulation of these pathways often results in obesity and diabetes ( Expert Rev. Mol. Med. 2012; 14:e1).
- phosphatidylinositol pathways e.g., PI3K/AKT, MAPK and AMPK pathways
- FIG. 60 shows changes a phylum levels wherein week 4 showed>95% confidence changes in the microbiome at the phylum level for the following: Treatment increased proteobacteria*, verrucomicrobia*, cyanobacteria*. Treatment decreased Bacteroidetes, firmicutes*, deferribacteres and spirochetes*.
- FIG. 61 shows significant differences for treatment versus control at a family level.
- FIG. 62 shows a principal coordinate analysis plot.
- FIG. 63 shows a significant enrichment in the pathways for biosynthesis of unsaturated fatty acids upon 4-week DA treatment (upper panel: individual data; lower panel: group data).
- FIG. 64 shows a significant enrichment in the pathways for metabolism of arachidonic acid upon 4-week DA treatment (upper panel: individual data; lower panel: group data).
- FIG. 65 shows a significant enrichment in the pathways for metabolism of cofactors and vitamins upon 4-week DA treatment (upper panel: individual data; lower panel: group data).
- FIG. 66 shows a significant enrichment in pathways for lysine degradation upon 4-week DA treatment (upper panel: individual data; lower panel: group data).
- FIG. 67 shows a significant enrichment in pathways for glycolysis and gluconeogenesis upon 4-week DA treatment (group data).
- FIG. 68 shows a significant enrichment in phosphatidylinositol signaling upon 4-week DA treatment (group data).
- FIG. 69 shows a significantly decreased signaling for arginine and ornithine metabolism upon 4-week DA treatment (upper panel: individual data; lower panel: group data).
- This example describes an in vivo study of denatonium acetate on body weight in leptin-deficient (ob/ob) mice.
- ob/ob mice a leptin-deficient mice fed with high-fat diet.
- the DA group (15 mice) were treated with a DA solution at a dose of 23.1 mg/kg BID.
- Body weights and body weight changes were determined at days 1, 3, 7, 10, 14, 21, 24 and 28. Food intake was determined on days 3, 7, 10, 14, 17, 21, 14 and 28. On day 28 blood samples were taken for cytokine analysis, HbA1c, HDL, LDL, insulin, and bile acids. Statistics were done by two-way repeated measures ANOVA followed by Tukey's multiple comparison post hoc test.
- Table 3A and FIG. 1 show body weight measurements from days 1-28.
- Table 3B and FIG. 2 show body weight changes from days 1-28.
- FIG. 3 shows the body weight change at day 28. There was no statistically significant difference in body weight change at day 28 between the two experimental groups.
- FIG. 4 shows fasting blood glucose levels at day 28. There was no statistically significant difference in blood fasting glucose level at day 28 between the two experimental groups.
- FIG. 5 shows HbA1c levels at day 28. There was no statistically significant difference in blood HbA1c levels at day 28 between the two experimental groups.
- FIG. 6 shows blood HDL levels at day 28. Animals treated with DA at 23.1 mg/kg showed a statistically significant decrease in blood HDL level at day 28 compared to vehicle-treated animals.
- FIG. 7 shows blood LDL cholesterol levels at day 28. There was no statistically significant difference in blood LDL levels at Day 28 between the two experimental groups.
- FIG. 8 shows blood total cholesterol level (LDL plus HDL) at day 28.
- Animals treated with DA at 23.1 mg/kg showed an almost significant decrease in blood total cholesterol levels at day 28 compared to vehicle-treated animals.
- FIG. 9 shows blood insulin levels at day 28. There was no statistically significant difference in blood insulin levels at day 28 between the two experimental groups.
- FIG. 10 shows blood bile acid levels at day 28. There was no statistically significant difference in blood bile acid levels at day 28 between the two experimental groups.
- FIG. 11 shows granulocyte number and percentage at pre-dose and at day 28, Although there was no statistically significant difference, DA-treated animals showed a trend of increasing change in granulocyte number as compared to vehicle-treated controls.
- FIG. 12 shows monocyte number and percentage at pre-dose and at day 28. Although there was no statistically significant difference, DA-treated animals showed a trend of increasing change in monocyte number and percentage as compared to vehicle-treated controls.
- FIG. 13 shows changes in lymphocyte and white blood cell number at pre-dose and at day 28. Although there was no statistically significant difference, DA-treated animals showed a trend of increasing change in lymphocyte and white blood cell numbers and percentage as compared to vehicle-treated controls.
- FIG. 14 shows cumulative food consumption over 28 days. There was no statistically significant difference in food consumption over 28 days between the two experimental groups.
- FIG. 15 shows various cytokines analysis in blood at day 28.
- KC cytokine-induced neutrophil chemoattractant (CXCL1); MCP-1: monocyte chemoattractant protein-1; MIP-1: macrophage inflammatory protein 1; M-CSF, macrophage colony-stimulating factor; MIP-2: macrophage inflammatory protein 2 (CXCL2); VEGF: vascular endothelial growth factor.
- KC/CXCL1 and M-CSF showed significant decreases with DA administration.
- FIG. 16 shows various cytokines analysis in blood at day 28.
- IP-10 IFN- ⁇ -Inducible Protein 10 (CXCL10).
- IL-10 and IL-12 showed significant decreases with DA administration.
- FIG. 17 shows various cytokines analysis in blood at day 28.
- G-CSF granulocyte colony-stimulating factor
- GM-CSF granulocyte-macrophage colony-stimulating factor
- IFN ⁇ interferon gamma
- IL-1 ⁇ , IL-1 ⁇ , IL-2 and IL-5 GM-CSF, IFN ⁇ , and IL-5 showed significant decreases with DA administration.
- Adipose tissue is considered a metabolic risk factor for these medical conditions, and contains a variety of immune cells, including macrophages, eosinophils, innate lymphoid cells (ILCs), T cells, and B cells.
- ILCs innate lymphoid cells
- T cells T cells
- B cells B cells.
- This immune cell accumulation induces a chronic low-grade inflammation, influencing metabolism of adipose tissue, promoting systemic inflammation, and impairing insulin action to cause systemic deleterious effects (Wisse, J. Am. Soc. Nephrol. 2004: 15(11):2792-800).
- proinflammatory factors have been demonstrated to play a role in this pathogenetic context (Saltiel and Olefsky, J. Clin. Invest. 2017; 127(1):1-4).
- a wide range of proinflammatory factors including cytokines and chemokines, show elevated circulating levels in individuals with metabolic syndromes, obesity, diabetes, or other metabolic disorders (Tchernof and Deseries, Physiol. Rev. 2013; 93(1):359-404).
- Some proinflammatory factors like TNF- ⁇ or IL-6, have been found to impair insulin action or affect lipid metabolism, thereby contributing to insulin resistance or disordered functions of fat storage (McLaughlin et al. J. Clin. Invest. 2017; 127(1):5-13).
- TAS2Rs Bitter taste receptors
- GPCR G protein-coupled receptor
- the body weight decrease in the DA treatment group may be attributed, at least partly, to the fact that DA-induced agonism at TAS2Rs on the immune cells inhibits the production of these cytokines, subsequently improving inflammation state in the adipose tissues and ameliorating dysfunction of lipid metabolism.
- This example provides the results of investigating DA to modulate immune response in a murine air pouch model of inflammation.
- Eight C57BL/6 mice were assigned to groups for gavage treatment (BID) of controls (distilled water), DA at a dose of 23.1 mg/kg BID (low dose DA), and DA at a dose of 96.4 mg/kg BID (high dose DA). What was measured was infiltrating cell counts with air pouch exudates, IL-6 levels in air pouch exudates by an ELISA assay (R&D Systems Cat. No. M6000B), and multiple cytokine analysis (Mouse 32Plex Kit MilliporeSigma Cat. No. MCYTMAG70PMX32BK).
- the subcutaneous air pouch is an in vivo model that can be used to study acute and chronic inflammation, the resolution of the inflammatory response, and the oxidative stress response. Injection of irritants into an air pouch in rats or mice induces an inflammatory response that can be quantified by the volume of exudate produced, the infiltration of cells, and the release of inflammatory mediators.
- the model presented in this unit has been extensively used to identify potential anti-inflammatory drugs.” It can be used to study localized inflammation without systemic effects. But in this case the drug was administered orally, by gavage BID. In earlier studies with this model, Romano et al. (1997) showed that dexamethasone (powerful anti-inflammatory steroid with severe side effects) by gavage decreased TNF levels.
- Test administration was 5 ml/kg body weight BID dosing with 8 hour intervals.
- the air pouch was created in each test BL6 mouse by sc injection of 1.5 ml/mouse of sterile air on day 0 and 1.5 ml/mouse of sterile air on day 3.
- Compounds (or control distilled water) were administered BID on day ⁇ 2.
- LPS (0.75 mg/animal in 1 ml endotoxin free PBS) was administered at hour 0 or one hour after dosing with test compounds.
- Plasma samples were collected at termination and exudates of the air pouches for all groups. Cell count analysis and IL-6 assays were conducted at the animal facility and plasma and exudate samples were sent out for cytokine analysis.
- Each group of distilled water control, 23.1 mg/kg DA and 92.4 mg/kg DA had 8 mice each.
- FIG. 18 shows a figure of infiltrating cell counts in air pouch exudates wherein pre-treatment with DA decreased infiltrating cell counts in air pouch exudates following LPS induction in a dose-dependent manner.
- Animals were pre-treated with DA at 96.4 mg/kg showed significantly lower infiltrating cell count as compared with those pre-treated with vehicle and the lower dose of DA between the results.
- FIG. 19 shows a figure of IL-6 levels in air pouch exudates wherein pre-treatment with DA decreased infiltrating cell counts in air pouch exudates following LPS induction in a dose-dependent manner.
- Animals were pre-treated with DA at 96.4 mg/kg showed significantly lower IL-6 levels as compared with those pre-treated with vehicle and the lower dose of DA between the results.
- FIGS. 20 - 27 shows the cytokines levels for G-CSF, Eotaxin, GM-CSF, IFNg, IL-1a, IL-1 ⁇ . IL-2, and IL-3, respectively.
- IL-10 showed significant reduction with the higher dose of DA.
- FIGS. 28 - 35 shows the cytokines levels for IL-4, IL-5, IL-7, IL-9, IL-10, IL-12p40, IL-12p70, and IL-13, respectively.
- IL-10 showed significant reduction with the higher dose of DA.
- FIGS. 36 - 43 shows the cytokines levels for IL-15, IL-17, LIF, LIX, IP-10, KC, MCP-1, and MCP-1 ⁇ , respectively.
- IL-17 showed significant reduction with the higher dose of DA.
- FIGS. 44 - 50 shows the cytokines levels for MIP-1b, MIP-2, M-CSF, MIG, RANTES, VEGF. and TNF-1a, respectively.
- TNF-1a showed significant reduction with the higher dose of DA.
- FIG. 51 shows a summary for the higher dose (orange) and the lower dose (blue) showing significance when demarcated with an asterisk.
- the pro-inflammatory biomarkers TNF ⁇ , IL-10, IL-10 and IL-17 showed significant dose-response reduction at the higher dose DA administration.
- This example provides the results of an in vivo study in a dextran sulfate sodium (DSS)-induced colitis in mice model.
- IBD Inflammatory bowel diseases
- a number of murine models of colitis have been developed. These models are tools to decipher underlying mechanisms of IBD pathogenesis as well as to evaluate potential therapeutics.
- DSS dextran sulfate sodium
- the dextran sulfate sodium (DSS) induced colitis model is widely used because of its many similarities with human ulcerative colitis.
- many existing IBD-approved drugs have been studied in this model to allow a comparison of new potential drug compounds as compared with existing drugs with approved IBD indications.
- C5BL/6 mice were divided into 5 groups of 3-10 mice, provided with standard mouse chow diet ad libitum, and housed up to 5 per cage.
- Dexamethasone 21-phosphate disodium salt (DMS; Alfa Aesar Catalog #J64083-1G, Lot R02F035) (was used as a positive control.
- Hemoccult kits were obtained from Beckman (Hemoccult SENSA kit).
- Dextran sodium sulfate (DSS) reagent grade MPI Catalog #160110, Lot #6046H, MW 36,000-50,000, CAS 9011-18-1) was supplemented in the water of certain groups to induced IBD-like symptoms. On day ⁇ 3 treatment began prior to DSS delivery.
- FIG. 53 shows body weight at day 10. Animals treated with 69.3 mg/kg DA, BID showed significant effect against DSS-induced body weight loss, as compared to vehicle.
- FIG. 54 shows fecal occult blood scores during the study period. Treatment with DA showed a significant main effect on fecal blood status.
- FIG. 55 shows fecal consistency score during the study period. Treatment with DA showed significant main effect on fecal consistency.
- FIG. 56 shows the combined fecal score during the study period. Treatment with DA showed a significant main effect on combined fecal status.
- FIGS. 57 and 58 shows colon weight and length at day 10, respectively. Although no significant difference was observed, treatment with high-dose of DA could counteract DSS-induced decrease in colon weight and length in mice.
- FIG. 59 shows spleen weight at day 10. Although no significant effect was observed, treatment with high-dose of DA showed a trend to counteract DSS-induced spleen weight loss in mice.
- DA small molecule oral TAS2R agonist
- AMLN Amylin Liver NASH
- ARD-101 (30 mg/mL in water) or vehicle (water) via intragastric gavage.
- DNA was isolated from fecal samples collected at week 0 and 4, and microbial ecology was evaluated using bTEFAP (bacterial tag-encoded FLX amplicon pyrosequencing).
- Operational taxonomic units were classified using BLAST against a curated NCBI database. Diversity within specific ecosystems and microbial community structures was analyzed with Qiime 2. Differences were determined by repeated measures ANOVA and post hoc pairwise comparisons using Tukey's test. Taxonomic classification data were evaluated with a dual hierarchal dendrogram.
- the phylum level there were significant increases in Proteobacteria, Verrucomicrobia, and Cyanobacteria and significant decreases in Firmicutes, Deferribacteres, and Spirochetes.
- This example provides an in vivo study to determine the effect of DA on mouse peritoneum macrophages.
- Peritoneal exudates were obtained from Balb/c female mice by lavage 4 days after an intraperitoneal injection of 4 ml sterile 4% thioglycollate broth. After washing with RPMI 1640 medium, the cell suspensions were centrifuged at 800 g at 4° C. for 5 min. The red blood cells were eliminated by ACK buffer and the cells were washed and resuspended in RPMI 1640 supplemented with 10% inactivated FBS, 10 mM HEPES, 2 mM glutamine, and 100 U/ml penicillin-100 mg/ml streptomycin.
- the peritoneal macrophages were plated in 24 well tissue culture plate (2 ⁇ 10 5 cells/mL/well) at 37° C. in a 5% CO 2 humidified atmosphere. Macrophages were precultured in serum-free RPMI 1640 medium for 24 h to reduce mitogenic effects. Macrophages were pretreated with various concentrations of DA for 1 h prior to LPS treatment and stimulated with LPS (100 ng/mL) for 24 h. Treatment groups were:
- Cytokines analyzed were—GM-CSF, IFN ⁇ , IL-1 ⁇ , IL-1 ⁇ , IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12 (p70), IL-13, IL-17A, KC/CXCL1, LIX, MCP-1, MIP-2, TNF- ⁇ .
- This example provides results of a study to evaluate the effect of denatonium acetate on a healthy mouse as measured by cytokine profile and routes of administration of DA.
- This example provides results of a study to evaluate the effect of denatonium acetate in a mouse acute lung injury plus hyperthermia model.
- the procedure was three groups of CD-1 mice given (1) saline by gavage for oral administration BID, (2) DA administered oral at a dose of 92.4 mg/kg BID and (3) was DA iv at 3 mg/kg iv bolus QD.
- Lung lavage fluid was measured and cytokine analysis.
- Statistics was one-way ANOVA followed by Tukey's multiple comparison post hoc test for data with normal distribution; Kruskal-Wallis test followed by Dunn's multiple comparison post hoc test for data with skewed distribution; and the ROUT method for identifying outliers.
- This example provides results of a second modified acute lung injury plus hyperthermia study to evaluate the effect of denatonium acetate.
- the same procedure was used as in Example 7.
- groups of six CD-1 mice each were treated prophylactically with vehicle or 92.4 mg/kg denatonium acetate (DA) (administered by twice-daily (BID) oral gavage (PO)) or with 3 mg/kg DA (administered by once-daily (QD) intraperitoneal (IP) injection).
- DA denatonium acetate
- BID twice-daily
- PO oral gavage
- IP intraperitoneal
- lung injury was induced by intratracheal instillation with 50 ⁇ L of 1 mg/mL bacterial lipopolysaccharide (LPS), and hyperthermia was induced by placing the animals in a 39° C. incubator.
- LPS bacterial lipopolysaccharide
- hyperthermia was induced by placing the animals in a 39° C. incubator.
- animals were euthanized and bronchoalveolar lavage fluid (BALF) was collected.
- the BALF specimens were assessed for cytokine concentrations (using a multiplex bead-based assay), and protein levels, and neutrophil counts (by fluorescence-activated cell sorting (FACS)). Additionally, lungs were collected, fixed, stained with Masson's trichrome, and assessed histologically.
- Oral dosing with 92.4 mg/kg DA yielded significant decreases (compared to vehicle) in the BALF concentrations of 7 of 32 tested cytokines, including IL-2, IL-3, IL-10. IL-13, MCSF, and MIG.
- IP dosing with 3 mg/kg DA provided significant decreases (compared to vehicle) in the BALF concentrations of 10 of 32 tested cytokines, including G-CSF, eotaxin, IL2, IL-3, IL-4, IL-13, IP-10, MCP-1, M-CSF, and MIG (see FIG. 73 ).
- BID PO treatment with 92.4 mg/kg DA or QD IP injection with 3 mg/kg DA provided significant attenuation of the accumulation of multiple cytokines in the lungs of this mouse model of acute lung injury, along with nominal activity in counteracting neutrophil infiltration and lung damage in these animals.
- This example provides results of a study of DA plus another compound (CQL) on body weight in diet-induced (DIO) mice.
- Adult C57BL/6NTac mice were fed with a high fat diet (60%).
- the study period was for 56 days+2-3 days testing period afterward.
- Body weight change measure 3 ⁇ per week, food and water consumption on days 0, 12, 28, 42 and 56. Metabolic biomarkers were measured on days 28 and 56. Cytokine analysis on Days 28 and 56.
- FIG. 74 shows DA treatment significantly reduced body weight gain at day 57 in DIO mice as compared to vehicle and CQL.
- FIG. 75 A shows that at Day 14, treatment with DA significantly reduced daily food intake in DIO mice as compared to vehicle and
- FIG. 75 B shows that treatment with DA significantly increased daily water intake at Day 28, while treatment with CQL significantly decreased daily water intake, as compared to vehicle.
- Treatment with DA did not show a significant effect on serum glucose levels in DIO mice.
- FIG. 76 shows that treatments with DA and CQL significantly reduced serum HbA1c level at Day 28, but considerably increased the HbA1c level at Day 56 in DIO mice.
- FIG. 77 shows that treatments with DA significantly reduced serum insulin level at Day 28 as compared to vehicle control in DIO mice.
- FIG. 79 shows that treatments with DA significantly increased serum GLP-1 levels in DIO mice at Days 7 and 56 as compared to vehicle control.
- FIG. 80 shows that treatments with DA significantly increased serum GLP-2 levels in DIO mice at Day 56 as compared to vehicle control.
- FIG. 81 shows that treatments with DA significantly increased serum CCK levels in DIO mice at Day 56 as compared to vehicle control.
- FIG. 82 shows that treatments with DA significantly increased serum PYY levels in DIO mice at Day 56 as compared to vehicle control.
- Leptin-deficient ob/ob mice exhibit hyperphagia and obesity, as well as hyperglycemia and hypertriglyceridemia, which are also found in patients with hyperphagia disorders such as Prader-Willi Syndrome and other monogenic and syndromic obesity disorders ( Diabetes. 2006 December; 55(12):3335-43 ; Clin Genet. 2005 March; 67(3):230-9 ; Biochim Biophys Acta. 2012 May; 1821(5):819-25). Therefore, ob/ob mice are a predictive in vivo model for these indications. This example provides results of a study of DA plus another compound (CQL) on body weight in leptin-deficient (ob/ob) mice.
- CQL another compound
- the study period was for 56 days+2-3 days testing period afterward.
- Body weight change measured 3 ⁇ per week, food intake was measure twice per week, metabolic biomarkers (blood glucose, blood insulin, blood HbA1c, HDL, LDL, triglyceride and bile acid) were measured at beginning and end of study. Cytokine analysis was measured at end on Day 56.
- FIG. 83 shows treatment with DA significantly decreased serum glucose levels in ob/ob mice. Treatment with DA showed no significant effect on serum HBA1c levels or insulin levels in ob/ob mice.
- FIG. 84 shows that treatments with DA significantly lowered serum triglyceride levels as compared to vehicle control in ob/ob mice.
- FIG. 85 shows that treatments with DA significantly increased serum bile acids levels as compared to vehicle control in ob/ob mice.
- FIG. 86 shows that treatments with DA significantly lowered serum LDL levels as compared to vehicle control in ob/ob mice. However, there were no significant effects on serum HDL levels.
Abstract
There is disclosed a method for treatment, prevention, and/or slowing of progression for various chronic inflammatory disorder groups including (1) type 2 diabetes group (metabolic syndrome (MET), obesity, hyperglycemia); (2) ARDS (acute respiratory distress syndrome); (3) chronic autoimmune inflammatory disorders (rheumatoid arthritis (RA), lupus, and psoriasis); (4) inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis; (5) metabolome-mediated diseases (atherosclerosis, hypertension, and congestive heart failure); and (6) hyperphagia disorders such as Prader-Willi Syndrome and other monogenic and syndromic obesity disorders including leptin pathway deficiencies, each comprising administering orally a pharmaceutical composition comprising a denatonium salt. The present disclosure is based on readouts from a series of studies tracking clusters of biomarkers levels to track mediators of inflammatory disorders and mediators of gut-signaling hormones in response to orally administered denatonium salts. There is further disclosed a pharmaceutical composition for treatment and prevention of various inflammatory conditions that can be tracked by pro-inflammatory biomarkers, comprising administering a pharmaceutical composition comprising a denatonium salt. Preferably, the pharmaceutical composition for daily oral administration comprises a denatonium salt delivering a daily total dose of from about 20 mg to about 5000 mg to a human adult BID. Preferably, the denatonium salt is selected from the group consisting of denatonium acetate, denatonium citrate, denatonium maleate and denatonium tartrate.
Description
- This application is a continuation of International Patent Application No. PCT/US2020/066835, filed Dec. 23, 2020, which claims the benefit of priority to U.S. Provisional Application No. 62/953,461, filed on Dec. 24, 2019, 62/971,202, filed on Feb. 6, 2020, 63/022,565, filed on May 10, 2020, and 63/092,453, filed on Oct. 15, 2020, the entire contents of each of which are incorporated herein by reference.
- The present disclosure provides a method for treatment, prevention, and/or slowing of progression for various chronic inflammatory disorder groups including (1)
type 2 diabetes group (metabolic syndrome (MET), obesity, hyperglycemia); (2) ARDS (acute respiratory distress syndrome); (3) chronic autoimmune inflammatory disorders (rheumatoid arthritis (RA), lupus, and psoriasis); (4) inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis; (5) metabolome-mediated diseases (atherosclerosis, hypertension, and congestive heart failure); and (6) hyperphagia disorders such as Prader-Willi Syndrome and other monogenic and syndromic obesity disorders including leptin pathway deficiencies, each comprising administering orally a pharmaceutical composition comprising a denatonium salt. The present disclosure is based on readouts from a series of studies tracking clusters of biomarkers levels to track mediators of inflammatory disorders and mediators of gut-signaling hormones in response to orally administered denatonium salts. The present disclosure further provides a pharmaceutical composition for treatment and prevention of various inflammatory conditions that can be tracked by pro-inflammatory biomarkers, comprising administering a pharmaceutical composition comprising a denatonium salt. Preferably, the pharmaceutical composition for daily oral administration comprises a denatonium salt delivering a daily total dose of from about 20 mg to about 5000 mg to a human adult BID. Preferably, the denatonium salt is selected from the group consisting of denatonium acetate, denatonium citrate, denatonium maleate and denatonium tartrate. - Over the past 40 years, global levels of obesity have more than doubled. As obesity predisposes to metabolic syndrome and has been linked to coronary heart disease, stroke,
type 2 diabetes, certain forms of cancer, and even to greater risk of severe illness and higher risk of death to coronavirus pandemic, this growing epidemic represents one of the most significant current global health challenges. In tandem with the emergence of this problem has been an increase in understanding the pathological mechanisms which link an obese state to the development of disease. Central to these mechanisms is the heightened state of systemic inflammation as a result of obesity, resulting in a multitude of pathologies. Therefore, there is a significant need for treatments and preventives to address appetite and inflammatory signals. The present disclosure addresses this need. - Various inflammatory diseases are currently treated with anti-tumor necrosis factor (TNF) (and anti-interleukin (IL)-6) proteins and antibodies. Such therapeutic proteins are approved for rheumatoid arthritis, polyarticular juvenile idiopathic arthritis (JIA) in children, psoriatic arthritis, lupus, ankylosing spondylitis (AS), chronic plaque psoriasis (Ps), panuveitis, IBD including ulcerative colitis and Crohn's disease, and many other diseases. These biological drugs act by binding and mopping up circulating TNFα (and IL-6) with an antibody or a fusion protein such as etanercept)(Embrel®. However, these anti-TNFα drugs and other biological drugs that indiscriminately bind and mop up inflammatory cytokines have severe side effects. The side effects are caused by inhibition of the vast majority of TNF signaling. As TNF has an immune surveillance function (that is also inhibited by these biological drugs), there is greater susceptibility to infection and decreased immune surveillance, including increased incidence of various infectious diseases and malignancies including leukemias and lymphomas listed on black box warning labels. Therefore, there is a need in the art for more cost-effective small molecule therapeutics that knock down (but not necessarily eliminate) circulating TNF. As protein-based therapeutics cannot be administered orally, there is a need in the art for an oral small molecule agent that is more subtle or self-limiting in their elimination of circulating TNF by preventing TNF production as a pro-inflammatory cytokine instead of mopping up existing and produced TNF indiscriminately.
- For example, adalimumab (Humira®) on the U.S. FDA approved label indicates the following side effects of increased risk for serious infections (i.e., including TB and infections caused by viruses, fungi, or bacteria), exacerbation of hepatitis B infection in carriers of the virus, allergic reactions, and various leukemias and lymphomas.
- Metabolic syndrome (METS) is a multiplex of factors increasing the risk of the development of
type 2 diabetes and cardiovascular disease. METS is a clustering of at least three of the five following medical conditions: (1) visceral obesity; (2) elevated blood pressure; (3) increased blood sugar; (4) high serum triglycerides; and (5) low serum high density lipoprotein (HDL). - According to the International Diabetes Foundation (IDF), metabolic syndrome presents with central obesity and any two of the following: (1) raised triglycerides (TG) of >150 mg/dL (1.7 mmol/L), or specific treatment for increased triglycerides; (2) reduced HDL of <40 mg/dL (1.03 mmol/L) in males<50 mg/dL (1.29 mmol/L in females; (3) raised blood pressure (BP) with systolic>130 or diastolic>85 mm Hg or treatment for hypertension and (4) raised fasting plasma glucose (FPG)>100 mg/dL (5.6 mmol/L) or previous diagnosis of
type 2 diabetes. - Metabolic syndrome may also be defined as presentation of hyperinsulinemia and any two of the following: (1) abdominal obesity (waist/hip ration>0.90 or
BMI 30 kg/m2), (2) dyslipidemia (TG>1.7 or HDL<0.9 mmol/L) and (3) hypertension (BP>140/90 mm Hg or use of antihypertensive medication). In a clinical study looking at carbohydrate restriction as a first line dietary intervention for METS, the study looked for significance in a group of biomarkers, including the inflammatory biomarkers TNFα, IL-6, and MCP-1 from fasting participants (Al-Sarraj et al., J. Nutrition 139(9):1667-1675, 2009). The study (n=20) found significance for MPC-1, ICAM-1, and TNFα, but not for IL-6. - METS affects 20-25% of the global adult population, including 35% of the U.S. adult population. METS is present in about 60% of U.S. residents aged>50. And METS correlates with a higher frequency of autoimmune diseases. Therefore, there is a need in the art to provide safer and effective METS therapeutics.
- Acute respiratory distress syndrome (ARDS) is a life-threatening disease, characterized by acute onset of hypoxia and pulmonary infiltrates, and incited by conditions such as sepsis, pneumonia, trauma, burns, pancreatitis and blood transfusion. ARDS causes diffuse lung inflammation which leads to increased pulmonary vascular permeability, pulmonary edema, and alveolar epithelial injury. The diagnosis of ARDS is made based on the following criteria: (1) acute onset; (2) bilateral lung infiltrates of a non-cardiac origin on chest x-ray or tomographic (CT) scan; and (3) moderate to severe impairment of oxygenation. Severe ARDS carries a mortality rate of 45%. The severity of the ARDS is defined by the degree of hypoxemia, which is calculated as the ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2). ARDS can be mild, moderate or severe as clarified by the Berlin definition of ARDS, wherein PaO2/FiO2 is 200-300 for mild, 100-199 for moderate and <100 for severe.
- In general, the development of ARDS can be separated into two phases: an initiator stage followed by an effector stage. The initiator phase of ARDS involves the release of inflammatory mediators (i.e., cytokines; complement and coagulation factors; and arachidonic acid metabolites) which promote systemic inflammation resulting in pulmonary neutrophil sequestration. The second stage, the effector phase, involves the activation of neutrophils with subsequent release of toxic oxygen radicals and proteolytic enzymes, specifically neutrophil elastase (NE). NE has the capacity to injure pulmonary endothelial cells and degrade products of the extracellular matrix, such as elastin, collagen, and fibronectin which comprise the lung basement membrane.
- Many diverse forms of ARDS exist with disparate etiologies and courses, although the end-state pathologies of these diverse forms are the same. Examples of clinical events that may precipitate different forms of ARDS include trauma, hemorrhage, diffuse pneumonia, virally induced pneumonia (including, but not limited to COVID-19 and SARS), inhalation of toxic gases, and sepsis. In the case of the 2020 COVID-19 pandemic, it is a viral pneumonia that drives the ARDS observed in many patients requiring critical care. Irrespective of initial cause, ARDS has the following in common: intrapulmonary fluid accumulation and exudates leading to diffuse alveolar damage and impaired gas exchange in the alveoli. What is common (irrespective of the initial cause of the ARDS) downstream is a worsening due to inflammation, fluid release, cell migration and proliferation as well as increases of proinflammatory cytokines.
- Viral respiratory infection is generally characterized by an incubation period typically 2-7 days in length, with infected individuals typically exhibiting high fevers, sometimes with accompanying chills, headache, malaise and myalgia. Viral infection of the lungs accounts for approximately 10-15% of ICU admissions in the US per year without a pandemic and is responsible for a significant percentage of deaths from influenza each year without a coronavirus pandemic. The 2020 pandemic from COVID-19 illustrates this course of disease progression. The illness progresses with the onset of a dry, non-productive cough or dyspnea, accompanied by or advancing into hypoxemia. A significant number of cases require intubation and mechanical ventilation. Furthermore, at the peak of respiratory illness, approximately 50% of infected individuals develop leukopenia and thrombocytopenia (MMWR Morb Mortal Wkly Rep. 2003 Mar. 28; 52(12):255-6).
- The patterns by which viral load spreads (such as a coronavirus or influenza virus) suggest droplet or contact transmission of a viral pathogen (N. Engl. J. Med. 2003 May 15; 348(20):1995-2005). SARS-1 and -2 have been associated etiologically with a virus, SARS-associated coronavirus (SARS-CoV) is a member of the coronavirus family of enveloped viruses which replicate in the cytoplasm of infected animal host cells. Coronaviruses are generally characterized as single-stranded RNA viruses having genomes of approximately 30,000 nucleotides (Science. 2003 May 30; 300(5624):1394-9). Coronaviruses fall into three known groups; the first two groups cause mammalian coronavirus infections, and the third group causes avian coronavirus infections (J. S. M. Peiris, in Medical Microbiology (Eighteenth Edition), 2012, 587-593). Coronaviruses are believed to be the causative agents of several severe diseases in many animals, for example, infectious bronchitis virus, feline infectious peritonitis virus and transmissible gastroenteritis virus, are significant veterinary pathogens (Viruses. 2019 January; 11(1): 59).
- Accordingly, a need exists for an effective treatment for patients diagnosed with SARS, patients infected with an infectious agent associated with SARS, such as patients infected with a SARS-CoV, or patients at imminent risk of contracting SARS, such as individuals that were exposed, or probably will be exposed in the near future, to an infectious agent associated with SARS.
- The prior art treatments for ARDS are inadequate. Accordingly, there is an urgent need for an effective treatment of ARDS.
- Intestinal microbiota have gained a lot of attention and disequilibrium of the gut microbiome has been associated with several diseases, depending on which groups of bacteria are increased or decreased. Atherosclerotic disease, with manifestations such as myocardial infarction and stroke, is the major cause of severe disease and death among subjects with the metabolic syndrome. The disease is believed to be caused by accumulation of cholesterol and recruitment of macrophages to the arterial wall and can thus be considered both as a metabolic and inflammatory disease. Since the first half of the 19th century infections have been suggested to cause or promote atherosclerosis by augmenting pro-atherosclerotic changes in vascular cells. However, there is still a need for better ways to early slow down an atherosclerotic change in vascular cells and associated diseases. The present invention provides a method for slowing down atherosclerotic changes in vascular cells by reducing gut signals that support atherosclerotic changes in vascular cells.
- The modulation of food behavior, including both control of appetite for some food compositions, and food preferences in favor of less fatty foods or with a lower caloric content, can provide a mechanism for the prevention of the development of metabolic disorders including cardiovascular diseases (Langley-Evans et al., Matern Child Nutr., 1, 142-148, 2005), particularly when food with a high caloric density or rich in fat, particularly saturated fat, is widely available, as happens in our developed societies.
- One of the more important signals playing a part in the maintenance of the energy balance and so of body weight is leptin, a circulating protein codified by the ob gene which is mainly expressed in the adipose tissue. Leptin plays a central role in the regulation of energy balance, inhibiting food intake and increasing energy waste (Zhang et al., Nature, 372, 425-432, 1994). This protein circulates in blood in a concentration that is proportional to the size of the fat depots; it passes through the blood-brain barrier by means of a saturable system and exerts most of its effects on energy balance at a central level, through the interaction of the protein with receptors located in hypothalamic neurons and in other regions of the brain (Tartaglia et al., Cell. 83, 1263-1271, 1995).
- Animals with defects in the leptin signaling axis, because they do not produce the functional protein or because they express defective forms of its receptor, are characterized by hyperphagia and massive obesity of early appearance, as well as by suffering diabetes, hypothermia and infertility. In humans, congenic defects in the leptin signaling (lack of leptin or of its receptor) are also related to morbid obesity of early appearance (Clement et al., Nature, 392, 398-401, 1998; Montague et al., Nature, 387, 903-908, 1997; Strobel et al., Nat. Genet., 18, 213-215, 1998). In this sense, the use of leptin in the treatment or prevention of diabetes mellitus (WO97/02004) whose direct cause is obesity was proposed. Although it was thought that the short-term anorexigenic role of leptin could contribute to controlling the problem of obesity and related disorders in obese people, unfortunately, leptin administration alone has been ineffective as a practical treatment, in part due to tolerance as well as compensatory upregulation of other pathways mediating hunger and satiety. Long term treatment outcome has remained unsatisfactory.
- With age, circulating levels of leptin increase (Matheny et al.,
Diabetes 1997, 46, 2035-9; Iossa et al., J Nutr. 1999, 129, 1593-6) and there is an impairment in sensitivity to this hormone (Qian et al., Proc. Soc. Exp. Biol. Med. 1998, 219, 160-5; Scarpace et al., Neuropharmacology, 2000, 39, 1872-9). Moreover, high levels of circulating leptin may favor the development of resistance to the anorexigenic effects of this hormone, which leads to perpetuating the development and maintenance of obesity and/or its complications. In fact, there is evidence suggesting that, in rats, leptin resistance would be the main determinant of body weight increase and age-related adiposity [Iossa et al., J. Nutr., 1999, 129, 1593-6]. However, although the concentration of circulating leptin is usually considered to be proportional to body fat mass and this mass usually increases as we grow old, there is evidence that the increase in leptinemia and the development of leptin resistance with age occurs, at least in part, independently of the increase in adiposity (Gabriely et al., Diabetes, 2002, 51, 1016-21). - High leptin circulating levels have been also associated in humans with an increase in the risk of cardiovascular disease [Ren, J. Endocrinol., 2004, 181, 1-10] and development of insulin resistance [Huang et al., Int. J. Obes. Relat. Metab. Disord., 2004, 28, 470-5], and this even independently of body mass index/adiposity.
- The present disclosure provides a method for treatment, prevention, and/or slowing of progression for various chronic inflammatory disorder groups including (1)
type 2 diabetes group (metabolic syndrome (MET), obesity, hyperglycemia); (2) ARDS (acute respiratory distress syndrome); (3) chronic autoimmune inflammatory disorders (rheumatoid arthritis (RA), lupus, and psoriasis); (4) inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis; (5) metabolome-mediated diseases (atherosclerosis, hypertension, and congestive heart failure); and (6) hyperphagia disorders such as Prader-Willi Syndrome and other monogenic and syndromic obesity disorders including leptin pathway deficiencies, each comprising administering orally a pharmaceutical composition comprising a denatonium salt. The present disclosure is based on readouts from a series of studies tracking clusters of biomarkers levels to track mediators of inflammatory disorders and mediators of gut-signaling hormones in response to orally administered denatonium salts. The present disclosure further provides a pharmaceutical composition for treatment and prevention of various inflammatory conditions that can be tracked by pro-inflammatory biomarkers, comprising administering a pharmaceutical composition comprising a denatonium salt. Preferably, the pharmaceutical composition for daily oral administration comprises a denatonium salt delivering a daily total dose of from about 20 mg to about 5000 mg to a human adult BID. Preferably, the denatonium salt is selected from the group consisting of denatonium acetate, denatonium citrate, denatonium maleate and denatonium tartrate. - The present disclosure provides a method for treatment, prevention and slowing down exacerbation of
type 2 diabetes including metabolic syndrome (MET), obesity, and hyperglycemia, comprising administering orally a pharmaceutic composition comprising a denatonium salt, wherein the denatonium salt is selected from the group consisting of denatonium acetate (DA), denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate. Preferably, the pharmaceutical composition further comprises from about 0.5 g to about 5 g acetic acid. More preferably, the dosage per day of the acetic acid for an adult is from about 1.5 g to about 3 g. Preferably the daily dosage of the denatonium salt for an adult is from about 20 mg to about 5000 mg or from about 5 mg/kg to about 150 mg/kg body weight per day. More preferably, the daily dosage of DA for an adult is from about 50 mg to about 1000 mg. Most preferably, the daily dosage of DA for an adult is from about 60 mg to about 500 mg, or to achieve a concentration in the GI tract of from about 10 parts per billion to about 50 ppm. The daily dose of the denatonium salt is administered once per day, twice per day or three times per day. - The present disclosure provides a method for treatment, prevention and slowing down exacerbation of acute pulmonary inflammatory disorders including ARDS, comprising administering orally a pharmaceutic composition comprising a denatonium salt, wherein the denatonium salt is selected from the group consisting of denatonium acetate (DA), denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate. Preferably, the pharmaceutical composition further comprises from about 0.5 g to about 5 g acetic acid. More preferably, the dosage per day of the acetic acid for an adult is from about 1.5 g to about 3 g. Preferably the daily dosage of the denatonium salt for an adult is from about 20 mg to about 5000 mg or from about 5 mg/kg to about 150 mg/kg body weight per day. More preferably, the daily dosage of DA for an adult is from about 50 mg to about 1000 mg. Most preferably, the daily dosage of DA for an adult is from about 60 mg to about 500 mg, or to achieve a concentration in the GI tract of from about 10 parts per billion to about 50 ppm. The daily dose of the denatonium salt is administered once per day, twice per day or three times per day.
- The present disclosure provides a method for treatment, prevention and slowing down exacerbation of chronic autoimmune inflammatory disorders group of indications selected from the group consisting of rheumatoid arthritis (RA), lupus, and psoriasis, comprising administering orally a pharmaceutic composition comprising a denatonium salt, wherein the denatonium salt is selected from the group consisting of denatonium acetate (DA), denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate. Preferably, the pharmaceutical composition further comprises from about 0.5 g to about 5 g acetic acid. More preferably, the dosage per day of the acetic acid for an adult is from about 1.5 g to about 3 g. Preferably the daily dosage of the denatonium salt for an adult is from about 20 mg to about 5000 mg or from about 5 mg/kg to about 150 mg/kg body weight per day. More preferably, the daily dosage of DA for an adult is from about 50 mg to about 1000 mg. Most preferably, the daily dosage of DA for an adult is from about 60 mg to about 500 mg, or to achieve a concentration in the GI tract of from about 10 parts per billion to about 50 ppm. The daily dose of the denatonium salt is administered once per day, twice per day or three times per day.
- The present disclosure provides a method for treatment, prevention and slowing down exacerbation of chronic IBD group of indications selected from the group consisting of Crohn's Disease, and ulcerative colitis, comprising administering orally a pharmaceutic composition comprising a denatonium salt, wherein the denatonium salt is selected from the group consisting of denatonium acetate (DA), denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate. Preferably, the pharmaceutical composition further comprises from about 0.5 g to about 5 g acetic acid. More preferably, the dosage per day of the acetic acid for an adult is from about 1.5 g to about 3 g. Preferably the daily dosage of the denatonium salt for an adult is from about 20 mg to about 5000 mg or from about 5 mg/kg to about 150 mg/kg body weight per day. More preferably, the daily dosage of DA for an adult is from about 50 mg to about 1000 mg. Most preferably, the daily dosage of DA for an adult is from about 60 mg to about 500 mg, or to achieve a concentration in the GI tract of from about 10 parts per billion to about 50 ppm. The daily dose of the denatonium salt is administered once per day, twice per day or three times per day.
- The present disclosure provides a method for treatment, prevention and slowing down exacerbation of metabolome mediated group of indications selected from the group consisting of atherosclerosis, hypertension, and congestive heart failure (CHF), comprising administering orally a pharmaceutic composition comprising a denatonium salt, wherein the denatonium salt is selected from the group consisting of denatonium acetate (DA), denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate. Preferably, the pharmaceutical composition further comprises from about 0.5 g to about 5 g acetic acid. More preferably, the dosage per day of the acetic acid for an adult is from about 1.5 g to about 3 g. Preferably the daily dosage of the denatonium salt for an adult is from about 20 mg to about 5000 mg or from about 5 mg/kg to about 150 mg/kg body weight per day. More preferably, the daily dosage of DA for an adult is from about 50 mg to about 1000 mg. Most preferably, the daily dosage of DA for an adult is from about 60 mg to about 500 mg, or to achieve a concentration in the GI tract of from about 10 parts per billion to about 50 ppm. The daily dose of the denatonium salt is administered once per day, twice per day or three times per day.
- The present disclosure provides a method for treatment, or slowing down exacerbation of a hyperphagia group of indications selected from the group consisting of Prader-Willi Syndrome and leptin pathway deficiencies, comprising administering orally a pharmaceutic composition comprising a denatonium salt, wherein the denatonium salt is selected from the group consisting of denatonium acetate (DA), denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate. Preferably, the pharmaceutical composition further comprises from about 0.5 g to about 5 g acetic acid. More preferably, the dosage per day of the acetic acid for an adult is from about 1.5 g to about 3 g. Preferably the daily dosage of the denatonium salt for an adult is from about 20 mg to about 5000 mg or from about 5 mg/kg to about 150 mg/kg body weight per day. More preferably, the daily dosage of DA for an adult is from about 50 mg to about 1000 mg. Most preferably, the daily dosage of DA for an adult is from about 60 mg to about 500 mg, or to achieve a concentration in the GI tract of from about 10 parts per billion to about 50 ppm. The daily dose of the denatonium salt is administered once per day, twice per day or three times per day.
-
FIG. 1 shows body weight over time with administration of DA compared to vehicle control. -
FIG. 2 shows body weight change over time with administration of DA compared to vehicle control. -
FIG. 3 shows the body weight change atday 28. There was no statistically significant difference in body weight change atDay 28 between the two experimental groups. -
FIG. 4 shows fasting blood glucose levels atday 28. There was no statistically significant difference in blood fasting glucose level atDay 28 between the two experimental groups. -
FIG. 5 shows HbA1c levels atday 28. There was no statistically significant difference in blood HbA1c levels atDay 28 between the two experimental groups. -
FIG. 6 shows blood HDL levels atday 28. Animals treated with DA at 23.1 mg/kg showed a statistically significant decrease in blood HDL level atDay 28 compared to vehicle-treated animals. -
FIG. 7 shows blood LDL cholesterol levels atday 28. There was no statistically significant difference in blood LDL levels atDay 28 between the two experimental groups. -
FIG. 8 shows blood total cholesterol level (LDL plus HDL) atday 28. Animals treated with DA at 23.1 mg/kg showed an almost significant decrease in blood total cholesterol levels atDay 28 compared to vehicle-treated animals. -
FIG. 9 shows blood insulin levels atday 28. There was no statistically significant difference in blood insulin levels atDay 28 between the two experimental groups. -
FIG. 10 shows blood bile acid levels atday 28. There was no statistically significant difference in blood bile acid levels atDay 28 between the two experimental groups. -
FIG. 11 shows granulocyte number and percentage at pre-dose and atday 28, Although there was no statistically significant difference, DA-treated animals showed a trend of increasing change in granulocyte number as compared to vehicle-treated controls. -
FIG. 12 shows monocyte number and percentage at pre-dose and atday 28. Although there was no statistically significant difference, DA-treated animals showed a trend of increasing change in monocyte number and percentage as compared to vehicle-treated controls. -
FIG. 13 shows changes in lymphocyte and white blood cell number at pre-dose and atday 28. Although there was no statistically significant difference, DA-treated animals showed a trend of increasing change in lymphocyte and white blood cell numbers and percentage as compared to vehicle-treated controls. -
FIG. 14 shows cumulative food consumption over 28 days. There was no statistically significant difference in food consumption over 28 days between the two experimental groups. -
FIG. 15 shows various cytokines analysis in blood atday 28. KC: cytokine-induced neutrophil chemoattractant (CXCL1); MCP-1: monocyte chemoattractant protein-1; MIP-1: macrophageinflammatory protein 1; M-CSF, macrophage colony-stimulating factor; MIP-2: macrophage inflammatory protein 2 (CXCL2); VEGF: vascular endothelial growth factor. KC or CXCL1 and M-CSF showed significant decreases with DA administration. -
FIG. 16 shows various cytokines analysis in blood atday 28. IP-10: IFN-γ-Inducible Protein 10 (CXCL10). IL-10 and IL-12 showed significant decreases with DA administration. -
FIG. 17 shows various cytokines analysis in blood atday 28. G-CSF: granulocyte colony-stimulating factor; GM-CSF: granulocyte-macrophage colony-stimulating factor; IFNγ: interferon gamma; IL-1α, IL-1β, IL-2 and IL-5. GM-CSF, IFNγ, and IL-5 showed significant decreases with DA administration. -
FIG. 18 shows a figure of infiltrating cell counts in air pouch exudates wherein pre-treatment with DA decreased infiltrating cell counts in air pouch exudates following LPS induction in a dose-dependent manner. Animals were pre-treated with DA at 96.4 mg/kg showed significantly lower infiltrating cell count as compared with those pre-treated with vehicle and the lower dose of DA between the results. -
FIG. 19 shows a figure of IL-6 levels in air pouch exudates wherein pre-treatment with DA decreased infiltrating cell counts in air pouch exudates following LPS induction in a dose-dependent manner. Animals were pre-treated with DA at 96.4 mg/kg showed significantly lower IL-6 levels as compared with those pre-treated with vehicle and the lower dose of DA between the results. -
FIGS. 20-27 show the cytokines levels for G-CSF, Eotaxin, GM-CSF, IFNγ, IL-1a, IL-1b, IL-2, and IL-3, respectively. In this group of cytokines, IL-1b showed significant reduction with the higher dose of DA. -
FIGS. 28-35 show the cytokines levels for IL-4, IL-5, IL-7, IL-9, IL-10, IL-12p40, IL-12p70, and IL-13, respectively. In this group of cytokines, IL-10 showed significant reduction with the higher dose of DA. -
FIGS. 36-43 show the cytokines levels for IL-15, IL-17, LIF, LIX, IP-10, KC. MCP-1, and MCP-1a, respectively. In this group of cytokines, IL-17 showed significant reduction with the higher dose of DA. -
FIGS. 44-50 show the cytokines levels for MIP-1b, MIP-2, M-CSF, MIG, RANTES, VEGF, and TNF-1a, respectively. In this group of cytokines, TNF-1a showed significant reduction with the higher dose of DA. -
FIG. 51 shows a summary for the higher dose (orange) and the lower dose (blue) showing significance with an asterisk. -
FIG. 52 shows body weight changes during the study period. Treatment with DA showed a significant main effect on body weight (P=0.0052). -
FIG. 53 shows body weight atday 10. Animals treated with 69.3 mg/kg DA, BID showed significant effect against DSS-induced body weight loss, as compared to vehicle. -
FIG. 54 shows fecal occult blood scores during the study period. Treatment with DA showed a significant main effect on fecal blood status. -
FIG. 55 shows fecal consistency score during the study period. Treatment with DA showed significant main effect on fecal consistency. -
FIG. 56 shows the combined fecal score during the study period. Treatment with DA showed a significant main effect on combined fecal status. -
FIGS. 57 and 58 shows colon weight and length atday 10, respectively. Although no significant difference was observed, treatment with high-dose of DA could counteract DSS-induced decrease in colon weight and length in mice. -
FIG. 59 shows spleen weight atday 10. Although no significant effect was observed, treatment with high-dose of DA showed a trend to counteract DSS-induced spleen weight loss in mice. -
FIG. 60 shows changes a phylum levels whereinweek 4 showed>95% confidence changes in the microbiome at the phylum level for the following: Treatment increased proteobacteria*, verrucomicrobia*, cyanobacteria*. Treatment decreased Bacteroidetes, firmicutes*, deferribacteres and spirochetes*. (*significant differences from control or time 0). -
FIG. 61 shows significant differences for treatment versus control at a family level. -
FIG. 62 shows a principal coordinate analysis plot. -
FIG. 63A-B show a significant enrichment in the pathways for biosynthesis of unsaturated fatty acids upon 4-week DA treatment (upper panel: individual data; lower panel: group data). -
FIG. 64A-B show a significant enrichment in the pathways for metabolism of arachidonic acid upon 4-week DA treatment (upper panel: individual data; lower panel: group data). -
FIG. 65A-B show a significant enrichment in the pathways for metabolism of cofactors and vitamins upon 4-week DA treatment (upper panel: individual data; lower panel: group data). -
FIG. 66A-B show a significant enrichment in pathways for lysine degradation upon 4-week DA treatment (upper panel: individual data; lower panel: group data). -
FIG. 67 shows a significant enrichment in pathways for glycolysis and gluconeogenesis upon 4-week DA treatment (group data). -
FIG. 68 shows a significant enrichment in phosphatidylinositol signaling upon 4-week DA treatment (group data). -
FIG. 69A-B show a significantly decreased signaling for arginine and ornithine metabolism upon 4-week DA treatment (upper panel: individual data; lower panel: group data). -
FIGS. 70A-C show graphs comparing biomarkers across many studies by family, showing decreased mean percentages. - In
FIG. 71 , it should be noted that clusters of multiple biomarkers predict effectiveness for each disease indication and that grouping is shown inFIG. 71 . -
FIGS. 72 and 73 shows cytokine profiles in lung lavage fluids from the data in Examples 7 and 8, respectively. -
FIG. 74 shows DA treatment significantly reduced body weight gain atday 57 in DIO mice as compared to vehicle and CQL. -
FIG. 75A shows that atDay 14, treatment with DA significantly reduced daily food intake in DIO mice as compared to vehicle. -
FIG. 75B shows that treatment with DA significantly increased daily water intake atDay 28, while treatment with CQL significantly decreased daily water intake, as compared to vehicle, both from Example 9. -
FIG. 76 shows that treatments with DA and CQL significantly reduced serum HbA1c level atDay 28, but considerably increased the HbA1c level atDay 56 in DIO mice. -
FIG. 77 shows that treatments with DA significantly reduced serum insulin level atDay 28 as compared to vehicle control in DIO mice. - In
FIG. 78 although no significant difference was observed, treatment with DA resulted in noticeable decrease in serum LDL levels atdays -
FIG. 79 shows that treatments with DA significantly increased serum GLP-1 levels in DIO mice atDays -
FIG. 80 shows that treatments with DA significantly increased serum GLP-2 levels in DIO mice atDay 56 as compared to vehicle control. -
FIG. 81 shows that treatments with DA significantly increased serum CCK levels in DIO mice atDay 56 as compared to vehicle control. -
FIG. 82 shows that treatments with DA significantly increased serum PYY levels in DIO mice atDay 56 as compared to vehicle control. -
FIG. 83 shows treatment with DA significantly decreased serum glucose levels in ob/ob mice. -
FIG. 84 shows that treatments with DA significantly lowered serum triglyceride levels as compared to vehicle control in ob/ob mice. -
FIG. 85 shows that treatments with DA significantly increased serum bile acids levels as compared to vehicle control in ob/ob mice. -
FIG. 86 shows that treatments with DA significantly lowered serum LDL levels as compared to vehicle control in ob/ob mice. - The present disclosure provides a method for treatment, prevention, and/or slowing of progression for various chronic inflammatory disorder groups including (1)
type 2 diabetes group (metabolic syndrome (MET), obesity, hyperglycemia); (2) ARDS (acute respiratory distress syndrome); (3) chronic autoimmune inflammatory disorders (rheumatoid arthritis (RA), lupus, and psoriasis); (4) inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis; (5) metabolome-mediated diseases (atherosclerosis, hypertension, and congestive heart failure); and (6) hyperphagia disorders such as Prader-Willi Syndrome and other monogenic and syndromic obesity disorders including leptin pathway deficiencies, each comprising administering orally a pharmaceutical composition comprising a denatonium salt. The present disclosure is based on readouts from a series of studies tracking clusters of biomarkers levels to track mediators of inflammatory disorders and mediators of gut-signaling hormones in response to orally administered denatonium salts. The present disclosure further provides a pharmaceutical composition for treatment and prevention of various inflammatory conditions that can be tracked by pro-inflammatory biomarkers, comprising administering a pharmaceutical composition comprising a denatonium salt. Preferably, the pharmaceutical composition for daily oral administration comprises a denatonium salt delivering a daily total dose of from about 20 mg to about 5000 mg to a human adult BID. Preferably, the denatonium salt is selected from the group consisting of denatonium acetate, denatonium citrate, denatonium maleate and denatonium tartrate. - The present disclosure is based on a discovery of (1) a cluster of surprising results from what started as a weight loss in vivo study in a predictive ob/ob obesity mouse model with a denatonium salt and placebo controls. The data from several studies in various in vivo models showed that orally administered denatonium salt with an organic acid anion show treatment efficacy and showed significant anti-inflammatory effects first by measuring inflammatory cytokines in the blood and other fluids (e.g., air pouch exudates and lung lavage fluids) as biomarkers and then gut signaling peptides. The methods of treatment that oral administration (but not intravenous administration) provided data showing efficacy for methods of treatment, prevention and slowing down disease progression in indications including metabolic syndrome (METS), obesity (inflammatory mediated), ARDS, rheumatoid arthritis (RA), lupus, and psoriasis (Examples 1 and 2); (2) an in vivo study in a dextran sulfate sodium (DSS)-induced colitis in a mouse model showing treatment and prevention efficacy in indications including inflammatory bowel diseases (IBD), mainly comprising ulcerative colitis and Crohn's disease (Example 3); and (3) a four week microbiome study in mice fed a high fat diet showing treatment and prevention efficacy for atherosclerosis, hypertension, and congestive heart failure (Example 4 and below). A cluster of proinflammation-indicating cytokines measured achieved significant differences between drug administered mice and control mice. Weight loss showed strong trends to in vivo efficacy with DA administration but was not similarly statistically significant.
- The cytokine data provided herein show in the inflammatory bowel disease model (Example 3), and in an air pouch model for inflammatory diseases, that the study drug, DA, did exhibit therapeutic activity in three areas: (1) to treat or prevent METS, (2) to treat or prevent general inflammatory diseases including autoimmune diseases; (3) to treat inflammatory bowel diseases including Crohn's Disease and ulcerative colitis; and (4) to treat cardiovascular diseases such as atherosclerosis, hypertension and congestive heart failure from microbiome data. Therefore, the data achieved in these studies does have a story to tell and the story is that a denatonium salt pharmaceutical composition shows safety and efficacy to (1) treat or prevent METS; (2) treat obesity and effect weight loss; (3) treat autoimmune inflammatory conditions rheumatoid arthritis (RA) lupus, and psoriasis; (4), treat Crohn's Disease and inflammatory bowel disease (IBD); and (5) treat or slow disease progression for cardiovascular diseases of atherosclerosis, hypertension and congestive heart failure. Preferably, the denatonium salt is selected from the group consisting of denatonium acetate, denatonium citrate, denatonium maleate and denatonium tartrate. More preferably, the denatonium salt for treating the foregoing listed indication is administered orally from about 25 mg to about 500 mg per day to an adult BID.
- In addition, the Example 2 study provided surprising results of statistical significance in reducing IL-5 production, which indicates the effectiveness of the present pharmaceutical composition of denatonium salts including DA in treating ARDS.
- This example describes the synthesis of denatonium acetate (DA).
- To a reflux apparatus add 25 g of lidocaine, 60 ml of water and 17.5 g of benzyl chloride with stirring and heating in 70-90° C. The solution needs to be heated and stirred in the before given value for 24 h, the solution needs to be cooled down to 30° C. The unreacted reagents are removed with 3×10 mL of toluene. With stirring dissolve 65 g of sodium hydroxide into 65 mL of cold water and add it to the aqueous solution with stirring over the course of 3 h. Filter the mixture, wash with some water and dry in open air. Recrystallize in hot chloroform or hot ethanol.
- To a reflux apparatus 10 g of denatonium hydroxide (MW: 342.475 g/mol, 0.029 mol), 20 mL of acetone, and 2 g of acetic acid glacial (0.033 mol) dissolved in 15 mL of acetone is added, the mixture is stirred and heated to 35° C. for 3 h. Then evaporated to dryness and recrystallized in hot acetone.
- This provides an
immediate release 50 mg granule formulation of denatonium acetate monohydrate (DA) as a free base as an immediate gastric release oral pharmaceutical formulation. - Table 1 shows qualitative and quantitative formulation composition of DA.
-
Limits based on IID Max DA Potency Quality Quantity capsule- for Unit Stan- Func- (%) 50 mg Dose Ref- Ingredient dard tion w/w (mg/cap) (mg) erence Denatonium In- API 23.55 59.03 N/A N/A acetate house (20 mg mono- Den- hydrate atonium base) Povidone USP Binder 2.36 5.90 61.5 Oral— (KOLLIDON Capsule 30) Sugar NF Sub- 68.85 172.57 314.13 Oral— Spheres strate Capsule (VIVAPHA RM ® Sugar Spheres 35-45) Hypro- USP Binder 3.64 9.14 150 Oral— mellose Capsule (Methocel E5 Premium LV Hydroxy- propyl Methyl- cellulose) Talc USP Anti- 1.09 2.74 14 Oral— (MicroTalc tacking Capsule, MP 1538 agent coated USP Talc) pellets Talc (extra USP Flow 0.50 1.25 284.38 Oral— granular) aid Capsule (MicroTalc MP 1538 USP Talc) Total weight of beads 250.62 N/A N/A Hard USP Capsule N/A 73.3 107 Oral— Gelatin shell Capsule Capsule Shells; Cap: White Opaque: Body: White Opaque; Size: 1 Total weight of Filled Capsule 323.9 N/A N/A IID, the Inactive Ingredient Database; API, active pharmaceutical ingredient; USP, the US Pharmacopeia; NF, the National Formulary * Solvents such as Ethyl Alcohol USP 190 Proof (190 Proof Pure Ethyl Alcohol) and purified water (USP) were used for the preparation of drug solution and seal coating dispersion, but are removed during the manufacturing process. - The detailed manufacturing steps are described below.
- Drug layering process was performed in a Fluid bed granulator equipped with the rotor insert (rotor granulator). Drug solution was prepared by solubilizing Povidone K30 (Kollidon 30) and Denatonium Acetate in ethyl alcohol. The drug solution was sprayed tangentially on to the bed of sugar spheres (35/45 mesh) moving in a circular motion in the rotor granulator. The final drug loaded pellets were then dried for ten (10) minutes in the rotor granulator, discharged and screened through a #20 mesh.
- Seal coating dispersion was prepared by separately dissolving Hypromellose E5 in a mixture (1:1) of ethyl alcohol and purified water until a clear solution was obtained. The remaining quantity of ethyl alcohol was then added to the above solution followed by talc. The dispersion was mixed for 20 minutes to allow for uniform dispersion of talc. The seal coating dispersion was sprayed tangentially on to the drug loaded pellets to achieve 5% weight gain. The seal coated pellets were then dried for five (5) minutes in the rotor granulator, discharged and dried further in a tray dryer/oven at 55° C. for 2 hours. The seal coated pellets were then screened through a #20 mesh.
- The seal coated pellets were blended with talc screened through
mesh # 60 using a V-Blender for ten (10) minutes and discharged. The blended seal coated beads, Denatonium IR Pellets, were used for encapsulation. - The Denatonium IR pellets, 50 mg, were filled into
size 1, white opaque hard gelatin capsules using an auto capsule filling machine. Capsules were then passed through an in-line capsule polisher and metal detector. In-process controls for capsule weight and appearance was performed during the encapsulation process. Acceptable quality limit (AQL) sampling and testing was performed by Quality Assurance (QA) on a composite sample during the encapsulation process. Finished product composite sample was collected and analyzed as per specification for release testing. - 5. Packaging—Capsules, 50 mg-30 Counts
- The 50 mg capsules were packaged in 30 counts into 50/60 cc White HDPE round S-line bottles with 33 mm White CRC Caps. The bottles were torqued and sealed using an induction sealer.
- The many examples provided herein show the effect of the denatonium salts on various in vivo and in vitro models of various disease indications. In addition, blood samples were taken from the tested (and control) animals and various biomarkers were measured and compared.
FIGS. 70A-C show graphs comparing biomarkers across many studies. Table 2 groups the biomarkers by family, shows decreased mean percentages and shows which disease indications are impacted and predicted by each biomarker. It should be noted that clusters of multiple biomarkers predict effectiveness for each disease indication and that grouping is shown inFIG. 71 . -
TABLE 2 Decreased Percentage with PO 92.4 mg/kg DA Family Member BID Compared to Vehicle Nexus to Indications Chemokines Eotaxin −18.6% Hyperphagia disorders such as Prader- Willi Syndrome and other monogenic and syndromic obesity disorders including leptin pathway deficiencies MIP-2 −76.3% Type 2 diabetes group (metabolic syndrome, obesity, hyperglycemia) ARDS KC −21.6% Type 2 diabetes group (metabolic syndrome, obesity, hyperglycemia) ARDS MCP-1 −24.2% Type 2 diabetes group (metabolic syndrome, obesity, hyperglycemia) Chronic autoimmune inflammatory disorders (rheumatoid arthritis, lupus, and psoriasis) Inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis ARDS Hyperphagia disorders such as Prader- Willi Syndrome and other monogenic and syndromic obesity disorders including leptin pathway deficiencies MIP-1α −3.4% ARDS MIP-1β −10.2% ARDS Chronic autoimmune inflammatory disorders (rheumatoid arthritis, lupus, and psoriasis) RANTES −20.6% ARDS Hyperphagia disorders such as Prader- Willi Syndrome and other monogenic and syndromic obesity disorders including leptin pathway deficiencies Metablome-mediated diseases (atherosclerosis, hypertension, and congestive heart failure) LIX −7.3% Type 2 diabetes group (metabolic syndrome, obesity, hyperglycemia) ARDS Inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis Chronic autoimmune inflammatory disorders (rheumatoid arthritis, lupus, and psoriasis) MIG −13.2% ARDS Inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis CSFs GM-CSF −2.3% Chronic autoimmune inflammatory disorders (rheumatoid arthritis, lupus, and psoriasis) Inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis ARDS G-CSF −37.5% Chronic autoimmune inflammatory disorders (rheumatoid arthritis, lupus, and psoriasis) Inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis ARDS Interleukins IL-1α −18.2% ARDS IL-1β −12.0% Hyperphagia disorders such as Prader- Willi Syndrome and other monogenic and syndromic obesity disorders including leptin pathway deficiencies ARDS Inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis IL-3 −74.5% ARDS IL-5 −29.1% Type 2 diabetes group (metabolic syndrome, obesity, hyperglycemia) Inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis IL-6 −34.2% ARDS Chronic autoimmune inflammatory disorders (rheumatoid arthritis, lupus, and psoriasis) Inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis Hyperphagia disorders such as Prader- Willi Syndrome and other monogenic and syndromic obesity disorders including leptin pathway deficiencies Metabolome-mediated diseases (atherosclerosis, hypertensin, and congestive heart failure) Type 2 diabetes group (metabolic syndrome, obesity, hyperglycemia) IL-10 −92.5% ARDS IL-12 (p70) −28.0% ARDS Metabolome-mediated diseases (atherosclerosis, hypertension, and congestive heart failure) Chronic autoimmune inflammatory disorders (rheumatoid arthritis, lupus, and psoriasis) IL-17 −21.2% ARDS Chronic autoimmune inflammatory disorders (rheumatoid arthritis, lupus, and psoriasis) Inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis Metabolome-mediated diseases (atherosclerosis, hypertension, and congestive heart failure) Type 2 diabetes group (metabolic syndrome, obesity, hyperglycemia) IFNs IFN-γ −37.3% Metabolome-mediated diseases (atherosclerosis, hypertension, and congestive heart failure) Type 2 diabetes group (metabolic syndrome, obesity, hyperglycemia) Chronic autoimmune inflammatory disorders (rheumatoid arthritis, lupus, and psoriasis) ARDS Inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis - There were changes in the microbiome in a mice model using a high-fat diet after 4 weeks of treatment with and without administering DA orally. The high fat diet itself induced extensive changes in the microbial populations in all groups. Importantly though, there was a pronounced difference between the DA treatment group and the control group at
week 4. - Classifications of the different organisms that changed in the control and treatment groups at 4 weeks and observed extensive changes in the primary or dominant phylum groups of bacteria, as well as on a family and genus level were made. For example, Firmicutes were dramatically reduced in the treatment group while Proteobacteria and Verrucomicrobia were dramatically increased. The diversity at 4 weeks dropped over the study course in both control and treatment group due to dietary impact. The treatment group had further significantly reduced overall diversity compared to control at 4 weeks, indicating an increase in specialized populations.
- The genetic potential of treatment-induced changes in relation to predicted physiological and metabolic pathways were aligned with observed benefits of treatment with DA with regards to attenuating inflammation and metabolic syndrome. The majority of the pathways being impacted were directly related to a decrease in inflammation and are known to be beneficial to cardiovascular health and other conditions related to the metabolic syndrome in humans. Observations included:
-
- Increased metabolism of unsaturated fatty acids
- Increased metabolism of arachidonic acid
- Increased metabolism of cofactors and vitamins
- Increased lysine degradation
- Increased glycolysis and gluconeogenesis
- Increased phosphatidylinositol signaling
- Decreased arginine and ornithine metabolism
Below Changes from Phylum à Family à Genus Level
- Genetic Potential 1: Increased metabolism of unsaturated fatty acids. There was a significant enrichment in pathways for biosynthesis of unsaturated fatty acids. Accumulating evidence supports a benefit of dietary unsaturated fatty acids over saturated fatty acids to improve cardiovascular health (Front Pharmacol. 2018; 9:1082; Circulation. 2017; 136(3):e1-e23; Ann. Intern. Med. 2014; 160(6):398-406).
- Genetic Potential 2: Increased metabolism of arachidonic acid. Arachidonic acid metabolites are important factors in the initiation and resolution of inflammation, and have been linked to the pathophysiology of obesity, diabetes mellitus, nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), and cardiovascular diseases (Int. J. Mol. Sci. 2018; 19(11): 3285).
- Genetic Potential 3: Increased metabolism of cofactors and vitamins. Increase in production of cofactors and vitamins have interactive effects. Cofactors, including 1-carnitine, nicotinamide riboside (NR), 1-serine, and N-acetyl-1-cysteine (NAC), have been demonstrated in human clinical studies to improve altered biological functions associated with different human diseases (Nutrients. 2019; 11(7):1578). Multiple vitamins and their derivatives have therapeutic potential for prevention and treatment of metabolic syndrome diseases, including diabetes mellitus (Can. J. Physiol. Pharmacol. 2015; 93(5):355-62; Endocr. Metab. Immune Disord. Drug Targets. 2015; 15(1):54-63).
- Genetic Potential 4: Increased lysine degradation. Major end products of lysine degradation are bacterial butyrate (Annu. Rev. Biochem. 1981; 50:23-40), which has been shown to prevent atherosclerosis by maintaining gut barrier function (Nat. Microbiol. 2018; 3(12):1332-1333). Another end product, acetate, has also similar effects to reduce inflammation (J. Atheroscler. Thromb. 2017; 24(7):660-672).
- Genetic Potential 5: Increased glycolysis and gluconeogenesis. Short chain fatty acid (SCFA) production in bacteria is sequential from glycolysis of glucose to pyruvate, to acetyl coenzyme A (CoA), and eventually to acetic acid, propionic acid, and butyric acid (J. Lipid Res. 2016; 57(6):943-54). This regulation ties in with previously noted pathways including lysine degradation.
- Genetic Potential 6: Increased phosphatidylinositol signaling. There was a significant phosphatidylinositol pathway upregulation. It has been documented that phosphatidylinositol pathways (e.g., PI3K/AKT, MAPK and AMPK pathways) are essential for glucose homeostasis. Moreover, deregulation of these pathways often results in obesity and diabetes (Expert Rev. Mol. Med. 2012; 14:e1).
- Genetic Potential 7: Decreased arginine and ornithine metabolism. We observed that arginine and ornithine metabolism pathways are significantly reduced. A randomized study proposed that high arginine levels were associated with higher risk of ischemic heart disease (Am. Heart J. 2016; 182:54-61), and accumulation of ornithine is also involved in pathogenesis of several metabolic diseases (Biomed. Pharmacother. 2017; 86:185-194).
-
FIG. 60 shows changes a phylum levels whereinweek 4 showed>95% confidence changes in the microbiome at the phylum level for the following: Treatment increased proteobacteria*, verrucomicrobia*, cyanobacteria*. Treatment decreased Bacteroidetes, firmicutes*, deferribacteres and spirochetes*. - *significant differences from control or
time 0 -
FIG. 61 shows significant differences for treatment versus control at a family level. -
- Genus significantly different between treatment at 4 weeks versus baseline and control.
- Significantly Increased
- Parabacteroides
- Escherichia
- Erysipelatoclostridium
- Peptoclostridium-
- Sutterella
- Shigella
- Brenneria
- Significantly Decreased
- Lachnoclostridium
- Barnesiella
- Clostridium
- Oscillospira
- Dorea
- Candidatus soleaferrea
- Dehalobacterium
- Oscillibacter
- Flavonifractor
-
FIG. 62 shows a principal coordinate analysis plot. -
FIG. 63 shows a significant enrichment in the pathways for biosynthesis of unsaturated fatty acids upon 4-week DA treatment (upper panel: individual data; lower panel: group data). -
FIG. 64 shows a significant enrichment in the pathways for metabolism of arachidonic acid upon 4-week DA treatment (upper panel: individual data; lower panel: group data). -
FIG. 65 shows a significant enrichment in the pathways for metabolism of cofactors and vitamins upon 4-week DA treatment (upper panel: individual data; lower panel: group data). -
FIG. 66 shows a significant enrichment in pathways for lysine degradation upon 4-week DA treatment (upper panel: individual data; lower panel: group data). -
FIG. 67 shows a significant enrichment in pathways for glycolysis and gluconeogenesis upon 4-week DA treatment (group data). -
FIG. 68 shows a significant enrichment in phosphatidylinositol signaling upon 4-week DA treatment (group data). -
FIG. 69 shows a significantly decreased signaling for arginine and ornithine metabolism upon 4-week DA treatment (upper panel: individual data; lower panel: group data). - This example describes an in vivo study of denatonium acetate on body weight in leptin-deficient (ob/ob) mice. Adult leptin-deficient mice (homozygote, ob/ob mice) fed with high-fat diet. There was a vehicle control group (15 mice) that were treated with distilled water by gavage BID. The DA group (15 mice) were treated with a DA solution at a dose of 23.1 mg/kg BID.
- Body weights and body weight changes were determined at
days days day 28 blood samples were taken for cytokine analysis, HbA1c, HDL, LDL, insulin, and bile acids. Statistics were done by two-way repeated measures ANOVA followed by Tukey's multiple comparison post hoc test. - Table 3A and
FIG. 1 show body weight measurements from days 1-28. -
TABLE 3A ANOVA table SS DF METS F (DFn, DFd) P value Time × 28.21 8 3.527 F (8, 224) = 1.833 P = 0.0721 Treatment Time 2775 8 346.9 F (1.210, 33.89) = P < 0.0001 180.3 Treatment 314.9 1 314.9 F (1, 28) = 2.053 P = 0.1630 Subject 4296 28 153.4 F (28, 224) = 79.73 P < 0.0001 Residual 431.1 224 1.924 Drug treatment showed no significant main effect on body weight in ob/ob mice [F (1, 28) = 2.076, P = 0.163]. - Table 3B and
FIG. 2 show body weight changes from days 1-28. -
TABLE 3B ANOVA table SS DF METS F (DFn, DFd) P value Time × 28.21 8 3.527 F (8, 224) = 1.833 P = 0.0721 Treatment Time 2775 8 346.9 F (1.210, 33.89) = P < 0.0001 180.3 Treatment 120.0 1 120.0 F (1, 28) = 2.809 P = 0.1049 Subject 1196 28 42.72 F (28, 224) = 22.20 P < 0.0001 Residual 431.1 224 1.924 Drug treatment showed no significant main effect on body weight change in ob/ob mice [F (1, 28) = 3.849, P = 0.105]. -
FIG. 3 shows the body weight change atday 28. There was no statistically significant difference in body weight change atday 28 between the two experimental groups. -
FIG. 4 shows fasting blood glucose levels atday 28. There was no statistically significant difference in blood fasting glucose level atday 28 between the two experimental groups. -
FIG. 5 shows HbA1c levels atday 28. There was no statistically significant difference in blood HbA1c levels atday 28 between the two experimental groups. -
FIG. 6 shows blood HDL levels atday 28. Animals treated with DA at 23.1 mg/kg showed a statistically significant decrease in blood HDL level atday 28 compared to vehicle-treated animals. -
FIG. 7 shows blood LDL cholesterol levels atday 28. There was no statistically significant difference in blood LDL levels atDay 28 between the two experimental groups. -
FIG. 8 shows blood total cholesterol level (LDL plus HDL) atday 28. Animals treated with DA at 23.1 mg/kg showed an almost significant decrease in blood total cholesterol levels atday 28 compared to vehicle-treated animals. -
FIG. 9 shows blood insulin levels atday 28. There was no statistically significant difference in blood insulin levels atday 28 between the two experimental groups. -
FIG. 10 shows blood bile acid levels atday 28. There was no statistically significant difference in blood bile acid levels atday 28 between the two experimental groups. -
FIG. 11 shows granulocyte number and percentage at pre-dose and atday 28, Although there was no statistically significant difference, DA-treated animals showed a trend of increasing change in granulocyte number as compared to vehicle-treated controls. -
FIG. 12 shows monocyte number and percentage at pre-dose and atday 28. Although there was no statistically significant difference, DA-treated animals showed a trend of increasing change in monocyte number and percentage as compared to vehicle-treated controls. -
FIG. 13 shows changes in lymphocyte and white blood cell number at pre-dose and atday 28. Although there was no statistically significant difference, DA-treated animals showed a trend of increasing change in lymphocyte and white blood cell numbers and percentage as compared to vehicle-treated controls. -
FIG. 14 shows cumulative food consumption over 28 days. There was no statistically significant difference in food consumption over 28 days between the two experimental groups. -
FIG. 15 shows various cytokines analysis in blood atday 28. KC: cytokine-induced neutrophil chemoattractant (CXCL1); MCP-1: monocyte chemoattractant protein-1; MIP-1: macrophageinflammatory protein 1; M-CSF, macrophage colony-stimulating factor; MIP-2: macrophage inflammatory protein 2 (CXCL2); VEGF: vascular endothelial growth factor. KC/CXCL1 and M-CSF showed significant decreases with DA administration. -
FIG. 16 shows various cytokines analysis in blood atday 28. IP-10: IFN-γ-Inducible Protein 10 (CXCL10). IL-10 and IL-12 showed significant decreases with DA administration. -
FIG. 17 shows various cytokines analysis in blood atday 28. G-CSF: granulocyte colony-stimulating factor; GM-CSF: granulocyte-macrophage colony-stimulating factor; IFNγ: interferon gamma; IL-1α, IL-1β, IL-2 and IL-5. GM-CSF, IFNγ, and IL-5 showed significant decreases with DA administration. - There is a direct link between chronic inflammation and development of metabolic syndrome and other metabolic disorders (McLaughlin et al. J. Clin. Invest. 2017; 127(1):5-13). Adipose tissue is considered a metabolic risk factor for these medical conditions, and contains a variety of immune cells, including macrophages, eosinophils, innate lymphoid cells (ILCs), T cells, and B cells. This immune cell accumulation induces a chronic low-grade inflammation, influencing metabolism of adipose tissue, promoting systemic inflammation, and impairing insulin action to cause systemic deleterious effects (Wisse, J. Am. Soc. Nephrol. 2004: 15(11):2792-800). Overproduction of proinflammatory factors by this immune cell accumulation has been demonstrated to play a role in this pathogenetic context (Saltiel and Olefsky, J. Clin. Invest. 2017; 127(1):1-4). A wide range of proinflammatory factors, including cytokines and chemokines, show elevated circulating levels in individuals with metabolic syndromes, obesity, diabetes, or other metabolic disorders (Tchernof and Després, Physiol. Rev. 2013; 93(1):359-404). Some proinflammatory factors, like TNF-α or IL-6, have been found to impair insulin action or affect lipid metabolism, thereby contributing to insulin resistance or disordered functions of fat storage (McLaughlin et al. J. Clin. Invest. 2017; 127(1):5-13).
- Bitter taste receptors (TAS2Rs) are members of the G protein-coupled receptor (GPCR) family, and are not only on the tongue but throughout the body (Lu et al. J. Gen. Physiol. 2017; 149(2): 181-197). In this study, we did observe that ob/ob mice treated with DA for 28 days showed a noticeable body weight decrease as compared to vehicle-treated controls; while there was no difference in average daily average individual food intake between these two groups of animals. Nevertheless, in DA-treated mice, a panel of cytokines, including GM-CSF, IFNγ, IL-5, IL-10, IL-12, KC, and M-CSF, showed significant decreases with DA administration. Therefore, the body weight decrease in the DA treatment group may be attributed, at least partly, to the fact that DA-induced agonism at TAS2Rs on the immune cells inhibits the production of these cytokines, subsequently improving inflammation state in the adipose tissues and ameliorating dysfunction of lipid metabolism.
- This example provides the results of investigating DA to modulate immune response in a murine air pouch model of inflammation. Eight C57BL/6 mice were assigned to groups for gavage treatment (BID) of controls (distilled water), DA at a dose of 23.1 mg/kg BID (low dose DA), and DA at a dose of 96.4 mg/kg BID (high dose DA). What was measured was infiltrating cell counts with air pouch exudates, IL-6 levels in air pouch exudates by an ELISA assay (R&D Systems Cat. No. M6000B), and multiple cytokine analysis (Mouse 32Plex Kit MilliporeSigma Cat. No. MCYTMAG70PMX32BK). Statistical analysis was done by a one-way ANOVA followed by Tukey's multiple comparison post hoc test for data with normal distribution, Kruskal-Wallis test followed by Dunn's multiple comparison post hoc test for data with skewed distribution, and the ROUT method for identifying outliers.
- Duarte et al., Current Protocols in Pharmacology, 5.6.1-5.6.8 Mar. 2012, describes “The subcutaneous air pouch is an in vivo model that can be used to study acute and chronic inflammation, the resolution of the inflammatory response, and the oxidative stress response. Injection of irritants into an air pouch in rats or mice induces an inflammatory response that can be quantified by the volume of exudate produced, the infiltration of cells, and the release of inflammatory mediators. The model presented in this unit has been extensively used to identify potential anti-inflammatory drugs.” It can be used to study localized inflammation without systemic effects. But in this case the drug was administered orally, by gavage BID. In earlier studies with this model, Romano et al. (1997) showed that dexamethasone (powerful anti-inflammatory steroid with severe side effects) by gavage decreased TNF levels.
- Test administration was 5 ml/kg body weight BID dosing with 8 hour intervals. The air pouch was created in each test BL6 mouse by sc injection of 1.5 ml/mouse of sterile air on
day 0 and 1.5 ml/mouse of sterile air onday 3. Compounds (or control distilled water) were administered BID on day −2. LPS (0.75 mg/animal in 1 ml endotoxin free PBS) was administered athour 0 or one hour after dosing with test compounds. Plasma samples were collected at termination and exudates of the air pouches for all groups. Cell count analysis and IL-6 assays were conducted at the animal facility and plasma and exudate samples were sent out for cytokine analysis. Each group of distilled water control, 23.1 mg/kg DA and 92.4 mg/kg DA had 8 mice each. -
FIG. 18 shows a figure of infiltrating cell counts in air pouch exudates wherein pre-treatment with DA decreased infiltrating cell counts in air pouch exudates following LPS induction in a dose-dependent manner. Animals were pre-treated with DA at 96.4 mg/kg showed significantly lower infiltrating cell count as compared with those pre-treated with vehicle and the lower dose of DA between the results. -
FIG. 19 shows a figure of IL-6 levels in air pouch exudates wherein pre-treatment with DA decreased infiltrating cell counts in air pouch exudates following LPS induction in a dose-dependent manner. Animals were pre-treated with DA at 96.4 mg/kg showed significantly lower IL-6 levels as compared with those pre-treated with vehicle and the lower dose of DA between the results. -
FIGS. 20-27 shows the cytokines levels for G-CSF, Eotaxin, GM-CSF, IFNg, IL-1a, IL-1β. IL-2, and IL-3, respectively. In this group of cytokines, IL-10 showed significant reduction with the higher dose of DA. -
FIGS. 28-35 shows the cytokines levels for IL-4, IL-5, IL-7, IL-9, IL-10, IL-12p40, IL-12p70, and IL-13, respectively. In this group of cytokines, IL-10 showed significant reduction with the higher dose of DA. -
FIGS. 36-43 shows the cytokines levels for IL-15, IL-17, LIF, LIX, IP-10, KC, MCP-1, and MCP-1α, respectively. In this group of cytokines, IL-17 showed significant reduction with the higher dose of DA. -
FIGS. 44-50 shows the cytokines levels for MIP-1b, MIP-2, M-CSF, MIG, RANTES, VEGF. and TNF-1a, respectively. In this group of cytokines, TNF-1a showed significant reduction with the higher dose of DA. - In summary,
FIG. 51 shows a summary for the higher dose (orange) and the lower dose (blue) showing significance when demarcated with an asterisk. Moreover, the pro-inflammatory biomarkers TNFα, IL-10, IL-10 and IL-17 showed significant dose-response reduction at the higher dose DA administration. - This example provides the results of an in vivo study in a dextran sulfate sodium (DSS)-induced colitis in mice model. Inflammatory bowel diseases (IBD), mainly comprising ulcerative colitis and Crohn's Disease, are complex and multifactorial diseases with unknown etiology. To study human IBD mechanistically, a number of murine models of colitis have been developed. These models are tools to decipher underlying mechanisms of IBD pathogenesis as well as to evaluate potential therapeutics. Among various chemically induced colitis models, the dextran sulfate sodium (DSS) induced colitis model is widely used because of its many similarities with human ulcerative colitis. Moreover, many existing IBD-approved drugs have been studied in this model to allow a comparison of new potential drug compounds as compared with existing drugs with approved IBD indications.
- C5BL/6 mice were divided into 5 groups of 3-10 mice, provided with standard mouse chow diet ad libitum, and housed up to 5 per cage. Dexamethasone 21-phosphate disodium salt (DMS; Alfa Aesar Catalog #J64083-1G, Lot R02F035) (was used as a positive control. Hemoccult kits were obtained from Beckman (Hemoccult SENSA kit). Dextran sodium sulfate (DSS) reagent grade (MPI Catalog #160110, Lot #6046H, MW 36,000-50,000, CAS 9011-18-1) was supplemented in the water of certain groups to induced IBD-like symptoms. On day −3 treatment began prior to DSS delivery. On
day 1 all mice were pre-weighed and given fresh 4-5% DSS in water every day for 5 days and water is then given for the remainder of the study to elicit disease. An additional control group was given water (no DSS) for the duration of the study (10 days). Body weight was measured daily, fecal blood status (hemoccult) was measured 3× per week,fecal consistency 3× per week and general health determined daily. Mice were sacrificed onday 10 and serum obtained for cytokine analysis and colon length and weight determined. There were two control groups of water only and DSS without drug treatment. There were two treatment groups at 69.3 mg/kg (n=10) bid and 23.1 mg/kg bid (n=10). -
FIG. 52 shows body weight changes during the study period. Treatment with DA showed a significant main effect on body weight (P=0.0052). -
FIG. 53 shows body weight atday 10. Animals treated with 69.3 mg/kg DA, BID showed significant effect against DSS-induced body weight loss, as compared to vehicle. -
FIG. 54 shows fecal occult blood scores during the study period. Treatment with DA showed a significant main effect on fecal blood status. -
FIG. 55 shows fecal consistency score during the study period. Treatment with DA showed significant main effect on fecal consistency. -
FIG. 56 shows the combined fecal score during the study period. Treatment with DA showed a significant main effect on combined fecal status. -
FIGS. 57 and 58 shows colon weight and length atday 10, respectively. Although no significant difference was observed, treatment with high-dose of DA could counteract DSS-induced decrease in colon weight and length in mice. -
FIG. 59 shows spleen weight atday 10. Although no significant effect was observed, treatment with high-dose of DA showed a trend to counteract DSS-induced spleen weight loss in mice. - In microbiome studies, low levels of Parabacteroides (protective commensal bacteria) correlate with atherosclerosis, higher Escherichia lead to coronary heart disease (CHD), Ruminococcaceae are often increased in patients with ACVD (atherosclerotic cardiovascular disease), and microbial-produced short chain fatty acids (SCFAs) lead to reduced atherosclerosis, inflammation, and moderate hypertension.
- The effect of a small molecule oral TAS2R agonist (DA) was investigated on microbial populations in a nonalcoholic steatohepatitis (NASH) mouse model. Two groups of 4-week-old male C57BL/6 mice (20/group) were fed Amylin Liver NASH (AMLN) diet and received daily doses of ARD-101 (30 mg/mL in water) or vehicle (water) via intragastric gavage. DNA was isolated from fecal samples collected at
week Qiime 2. Differences were determined by repeated measures ANOVA and post hoc pairwise comparisons using Tukey's test. Taxonomic classification data were evaluated with a dual hierarchal dendrogram. - The AMLN diet led to changes in microbial populations in both groups at
week 4. Significant increases/decreases at the phylum, family, and genus levels were observed in the DA group versus vehicle group atweek 4. For example, at the phylum level, there were significant increases in Proteobacteria, Verrucomicrobia, and Cyanobacteria and significant decreases in Firmicutes, Deferribacteres, and Spirochetes. There was significantly less diversity within ecosystems and microbial communities atweek 4 vsweek 0 in both treatment groups and the DA versus vehicle group at week 4 (p<0.05 for all comparisons). Genetic analysis showed that DA led to increased metabolism of unsaturated fatty acids and arachidonic acid, increased production of cofactors and vitamins; increased lysine degradation, glycolysis, gluconeogenesis, and phosphatidylinositol signaling; and decreased arginine and ornithine production. DA treatment-induced significant changes in physiological and metabolic pathways and mitigated the diet-induced decrease of SCFAs in feces. Overall findings are aligned with data showing that DA attenuates inflammation and metabolic syndrome. - This example provides an in vivo study to determine the effect of DA on mouse peritoneum macrophages. Peritoneal exudates were obtained from Balb/c female mice by
lavage 4 days after an intraperitoneal injection of 4 ml sterile 4% thioglycollate broth. After washing with RPMI 1640 medium, the cell suspensions were centrifuged at 800 g at 4° C. for 5 min. The red blood cells were eliminated by ACK buffer and the cells were washed and resuspended in RPMI 1640 supplemented with 10% inactivated FBS, 10 mM HEPES, 2 mM glutamine, and 100 U/ml penicillin-100 mg/ml streptomycin. The peritoneal macrophages were plated in 24 well tissue culture plate (2×105 cells/mL/well) at 37° C. in a 5% CO2 humidified atmosphere. Macrophages were precultured in serum-free RPMI 1640 medium for 24 h to reduce mitogenic effects. Macrophages were pretreated with various concentrations of DA for 1 h prior to LPS treatment and stimulated with LPS (100 ng/mL) for 24 h. Treatment groups were: -
TABLE 4 No. of Group Wells Treatment 1 6 Vehicle 2 6 LPS 3 6 LPS + SB203580 (Positive control) 4 6 LPS + ARD 101 (1 μM) 5 6 LPS + ARD 101 (10 μM) 6 6 LPS + ARD 101 (100 μM)) At 12 and 24 h time points of stimulation, ~200 ul of supernatant were removed and stored (−80° C.) for cytokine analysis (13 Plex). Cytokines analyzed were—GM-CSF, IFNγ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12 (p70), IL-13, IL-17A, KC/CXCL1, LIX, MCP-1, MIP-2, TNF-α. -
TABLE 5 reports the mean ± SD for each cytokine: Concen- tration Significance @12 Significance @24 cytokine DA (μM) hour LPS incubation hour LPS incubation GM-CSF 1/10/100 P = 0.029/no sig/no sig No sig/no sig/no sig IFNγ 1/10/100 P = 0.031/0.037/no sig No sig/no sig/no sig IL-1α 1/10/100 P = 0.021/0.036/no sig No sig/no sig/no sig IL-1β 1/10/100 P = 0.023/0.023/no sig No sig/no sig/no sig IL-2 1/10/100 P = 0.005/0.004/no sig No sig/no sig/no sig IL-4 1/10/100 P = 0.009/0.009/no sig No sig/no sig/no sig IL-6 1/10/100 P = 0.096/0.029/no sig No sig/no sig/no sig IL-7 1/10/100 P = 0.024/0.010/010 No sig/no sig/no sig IL-10 1/10/100 P = 0.045/0.026/0.015 No sig/no sig/no sig IL-12 (p70) 1/10/100 P = 0.017/0.007/0.008 No sig/no sig/no sig IL-13 1/10/100 P = 0.038/0.019/0.021 No sig/no sig/no sig IL-17A 1/10/100 P = 0.044/0.024/0.042 No sig/no sig/no sig KC/CXCL1 1/10/100 No sig/no sig/P = 0.022 No sig/no sig/no sig LIX 1/10/100 No sig/no sig/no sig No sig/no sig/no sig MCP-1 1/10/100 No sig/no sig/no sig No sig/no sig/no sig MIP-2 1/10/100 P = 0.081/0.021/0.033 No sig/no sig/no sig TNF-α 1/10/100 P = 0.059/0.024/0.033 No sig/no sig/no sig In summary, a 24-hour incubatin with LPS dis not elicit the significant differences as a 12 hour LPS incubatin. - This example provides results of a study to evaluate the effect of denatonium acetate on a healthy mouse as measured by cytokine profile and routes of administration of DA. The study groups were: (1) Vehicle group, N=12, treated with distilled water, gavage, BID; (2) DA oral low dose group, N=12, treated with DA at a dose of 23.1 mg/kg (salt weight), gavage, BID; (3) DA oral high dose group, N=12, treated with DA at a dose of 92.4 mg/kg (salt weight), gavage, BID; (4) DA IV low dose group, N=12, treated with DA at a dose of 1 mg/kg (salt weight), iv bolus, QD; (5) DA IV high dose group, N=12, treated with ARD-101 at a dose of 3 mg/kg (salt weight), iv bolus, QD.
- Firstly, there were no biomarker (cytokine) effects seen with either iv DA dose. It is safe to conclude that DA needs to be administered orally in order to show effect. Moreover, there were toxic side effects with only iv administration.
Group # 3 was the lower dose oral DA group and 4 was the higher dose oral DA group, Lower dose DA saw significant decreases in the cytokines (versus controls) for G-CSF (p=0.003), IL-1α (p=0.04), IL-1β (p=0.03), MCP-1 (p=0.005), MIP-2 (p=0.015), and VEGF (p=0.001). Higher dose DA saw significant decreases in the cytokines (versus controls) for GM-CSF (p=0.03), IL-9 (p=0.003), KC (p=0.05), and VEGF (p=0.001). This study confirms biomarker effects in normal mice and confirms that oral dosing, not iv, should be used. - This example provides results of a study to evaluate the effect of denatonium acetate in a mouse acute lung injury plus hyperthermia model. The procedure was three groups of CD-1 mice given (1) saline by gavage for oral administration BID, (2) DA administered oral at a dose of 92.4 mg/kg BID and (3) was DA iv at 3 mg/kg iv bolus QD. Lung lavage fluid was measured and cytokine analysis. Statistics was one-way ANOVA followed by Tukey's multiple comparison post hoc test for data with normal distribution; Kruskal-Wallis test followed by Dunn's multiple comparison post hoc test for data with skewed distribution; and the ROUT method for identifying outliers. Control or drug administered for 3 days, then LPS at 50 μL of 1 mg/ml delivered intratracheally with a Penn Century needle where a core temperature of 39 C at 24 hours post LPS and then sacrifice to measure lung lavage fluid protein concentration and serum cytokine levels.
- DA showed drastic but not significantly reduced protein concentration in lung lavage fluid for both the oral and iv doses. Cytokine profiles in lung lavage fluids are shown in
FIG. 72 where DA=ARD−101. - This example provides results of a second modified acute lung injury plus hyperthermia study to evaluate the effect of denatonium acetate. The same procedure was used as in Example 7. Starting three days before the induction of lung injury, groups of six CD-1 mice each were treated prophylactically with vehicle or 92.4 mg/kg denatonium acetate (DA) (administered by twice-daily (BID) oral gavage (PO)) or with 3 mg/kg DA (administered by once-daily (QD) intraperitoneal (IP) injection). On
Day 0, lung injury was induced by intratracheal instillation with 50 μL of 1 mg/mL bacterial lipopolysaccharide (LPS), and hyperthermia was induced by placing the animals in a 39° C. incubator. On Day 1 (i.e., 24 hours after induction), animals were euthanized and bronchoalveolar lavage fluid (BALF) was collected. The BALF specimens were assessed for cytokine concentrations (using a multiplex bead-based assay), and protein levels, and neutrophil counts (by fluorescence-activated cell sorting (FACS)). Additionally, lungs were collected, fixed, stained with Masson's trichrome, and assessed histologically. Three days of repeat PO dosing with 92.4 mg/kg DA (BID) or IP dosing with 3 mg/kg DA (QD) was well-tolerated in female CD-1 mice. Although two mice [one vehicle-dosed, one DA (92.4 mg/kg)-dosed] were found dead onDay 1, the timing of these mortalities (within 24 h after LPS instillation) suggested that the deaths reflected the instillation process, hyperthermia, or associated inflammation (rather than test article). This inference is consistent with the observation that deaths were seen both with vehicle and test article dosing. No other adverse clinical observations were noted during 3 days of test article administration. Oral dosing with 92.4 mg/kg DA yielded significant decreases (compared to vehicle) in the BALF concentrations of 7 of 32 tested cytokines, including IL-2, IL-3, IL-10. IL-13, MCSF, and MIG. IP dosing with 3 mg/kg DA provided significant decreases (compared to vehicle) in the BALF concentrations of 10 of 32 tested cytokines, including G-CSF, eotaxin, IL2, IL-3, IL-4, IL-13, IP-10, MCP-1, M-CSF, and MIG (seeFIG. 73 ). Oral and IP dosing with the indicated levels of DA was associated with nominal (but nonsignificant) changes in BALF protein concentrations; nominal decreases in BALF neutrophil counts (by FACS assay); and nominal decreases in the severity of lung pathology (by histological scoring). Thus, BID PO treatment with 92.4 mg/kg DA or QD IP injection with 3 mg/kg DA provided significant attenuation of the accumulation of multiple cytokines in the lungs of this mouse model of acute lung injury, along with nominal activity in counteracting neutrophil infiltration and lung damage in these animals. - This example provides results of a study of DA plus another compound (CQL) on body weight in diet-induced (DIO) mice. Adult C57BL/6NTac mice were fed with a high fat diet (60%). Vehicle group (N=15) were treated with distilled water by gavage BID, CQL (N=15) were treated at 50 mg/kg by gavage BID, and DA (N=15) at a dose of 92.4 mg/kg by gavage BID. The study period was for 56 days+2-3 days testing period afterward. Body
weight change measure 3× per week, food and water consumption ondays days Days Days Day 56. -
FIG. 74 shows DA treatment significantly reduced body weight gain atday 57 in DIO mice as compared to vehicle and CQL.FIG. 75A shows that atDay 14, treatment with DA significantly reduced daily food intake in DIO mice as compared to vehicle andFIG. 75B shows that treatment with DA significantly increased daily water intake atDay 28, while treatment with CQL significantly decreased daily water intake, as compared to vehicle. Treatment with DA did not show a significant effect on serum glucose levels in DIO mice.FIG. 76 shows that treatments with DA and CQL significantly reduced serum HbA1c level atDay 28, but considerably increased the HbA1c level atDay 56 in DIO mice.FIG. 77 shows that treatments with DA significantly reduced serum insulin level atDay 28 as compared to vehicle control in DIO mice. InFIG. 78 although no significant difference was observed, treatment with DA resulted in noticeable decrease in serum LDL levels atdays FIG. 79 shows that treatments with DA significantly increased serum GLP-1 levels in DIO mice atDays FIG. 80 shows that treatments with DA significantly increased serum GLP-2 levels in DIO mice atDay 56 as compared to vehicle control.FIG. 81 shows that treatments with DA significantly increased serum CCK levels in DIO mice atDay 56 as compared to vehicle control.FIG. 82 shows that treatments with DA significantly increased serum PYY levels in DIO mice atDay 56 as compared to vehicle control. - At
days 28 and 56 (28/56), serum cytokines were measured and showed significant increases for G-CSR (p=0.063/0.039), Eotaxin (p=0.031/no sig), IL-6 (p=0.041/no sig), IP-10 (p=0.013/no sig), and MIG (p=no sig/0.028). Many of the mice did not permit enough blood to be obtained to generate statistical significance. - Leptin-deficient ob/ob mice exhibit hyperphagia and obesity, as well as hyperglycemia and hypertriglyceridemia, which are also found in patients with hyperphagia disorders such as Prader-Willi Syndrome and other monogenic and syndromic obesity disorders (Diabetes. 2006 December; 55(12):3335-43; Clin Genet. 2005 March; 67(3):230-9; Biochim Biophys Acta. 2012 May; 1821(5):819-25). Therefore, ob/ob mice are a predictive in vivo model for these indications. This example provides results of a study of DA plus another compound (CQL) on body weight in leptin-deficient (ob/ob) mice. Vehicle group (N=14) were treated with distilled water by gavage BID, and DA (N=14) at a dose of 50 mg/kg by gavage BID. The study period was for 56 days+2-3 days testing period afterward. Body weight change measured 3× per week, food intake was measure twice per week, metabolic biomarkers (blood glucose, blood insulin, blood HbA1c, HDL, LDL, triglyceride and bile acid) were measured at beginning and end of study. Cytokine analysis was measured at end on
Day 56. - Treatment with DA showed no significant effect on body weight in ob/ob mice. Treatment with DA showed no significant effect on daily food consumption in ob/ob mice.
FIG. 83 shows treatment with DA significantly decreased serum glucose levels in ob/ob mice. Treatment with DA showed no significant effect on serum HBA1c levels or insulin levels in ob/ob mice.FIG. 84 shows that treatments with DA significantly lowered serum triglyceride levels as compared to vehicle control in ob/ob mice.FIG. 85 shows that treatments with DA significantly increased serum bile acids levels as compared to vehicle control in ob/ob mice.FIG. 86 shows that treatments with DA significantly lowered serum LDL levels as compared to vehicle control in ob/ob mice. However, there were no significant effects on serum HDL levels. - The DA group saw significant decreases in the cytokines (versus controls) at
day 56 for Eotaxin (p=0.047), and MIG (p=0.026). In addition, although no significant difference was observed, the DA group showed decreased levels for the following cytokines atday 56 as compared to the vehicle group: RANTES (decreased by 1.7%), IL-1β (decreased by 19.1%), IL-6 (decreased by 61.4%), and MCP-1 (decreased by 20.9%).
Claims (24)
1. A method for treatment, prevention and slowing down exacerbation of type 2 diabetes group of indications selected from the group consisting of metabolic syndrome (METS), obesity, and hyperglycemia, comprising administering orally a pharmaceutic composition comprising a denatonium salt, wherein the denatonium salt is selected from the group consisting of denatonium acetate (DA) denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate.
2. The method of claim 1 , wherein the pharmaceutical composition further comprises from about 0.5 g to about 5 g acetic acid.
3. The method of claim 1 , wherein the daily dosage of the denatonium salt for an adult is from about 20 mg to about 5000 mg.
4. The method of claim 3 , wherein the daily dosage of DA for an adult is from about 50 mg to about 1000 mg.
5. The method of claim 4 , wherein the daily dosage of DA for an adult is from about 60 mg to about 500 mg, or to achieve a concentration in the GI tract of from about 10 parts per billion to about 50 ppm.
6. The method of claim 1 , wherein the daily dose of the denatonium salt is administered once per day, twice per day or three times per day.
7. A method for treatment, prevention and slowing down exacerbation of acute pulmonary inflammatory disorders including ARDS, comprising administering orally a pharmaceutic composition comprising a denatonium salt, wherein the denatonium salt is selected from the group consisting of denatonium acetate (DA) denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate.
8. The method of claim 7 , wherein the pharmaceutical composition further comprises from about 0.5 g to about 5 g acetic acid.
9. The method of claim 7 , wherein the daily dosage of the denatonium salt for an adult is from about 20 mg to about 5000 mg.
10. The method of claim 9 , wherein the daily dosage of DA for an adult is from about 50 mg to about 1000 mg.
11. The method of claim 10 , wherein the daily dosage of DA for an adult is from about 60 mg to about 500 mg, or to achieve a concentration in the GI tract of from about 10 parts per billion to about 50 ppm.
12. The method of claim 7 , wherein the daily dose of the denatonium salt is administered once per day, twice per day or three times per day.
13. A method for treatment, prevention and slowing down exacerbation of chronic autoimmune inflammatory disorders group of indications selected from the group consisting of rheumatoid arthritis (RA), lupus, and psoriasis, comprising administering orally a pharmaceutic composition comprising a denatonium salt, wherein the denatonium salt is selected from the group consisting of denatonium acetate (DA) denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate.
14-18. (canceled)
19. A method for treatment, prevention and slowing down exacerbation of chronic inflammatory bowel diseases (IBD) group of indications selected from the group consisting of Crohn's Disease, and ulcerative colitis, comprising administering orally a pharmaceutic composition comprising a denatonium salt, wherein the denatonium salt is selected from the group consisting of denatonium acetate (DA) denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate.
20-24. (canceled)
25. A method for treatment, prevention and slowing down exacerbation of metabolome mediated group of indications selected from the group consisting of atherosclerosis, hypertension, and congestive heart failure (CHF), comprising administering orally a pharmaceutic composition comprising a denatonium salt, wherein the denatonium salt is selected from the group consisting of denatonium acetate (DA) denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate.
26-30. (canceled)
31. A method for treatment, or slowing down exacerbation of, hyperphagia group of indications selected from the group consisting of Prader Willi, and leptin pathway deficiencies, comprising administering orally a pharmaceutic composition comprising a denatonium salt, wherein the denatonium salt is selected from the group consisting of denatonium acetate (DA) denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate.
32. The method of claim 31 , wherein the pharmaceutical composition further comprises from about 0.5 g to about 5 g acetic acid.
33. The method of claim 31 , wherein the daily dosage of the denatonium salt for an adult is from about 20 mg to about 5000 mg.
34. The method of claim 33 , wherein the daily dosage of DA for an adult is from about 50 mg to about 1000 mg.
35. The method of claim 34 , wherein the daily dosage of DA for an adult is from about 60 mg to about 500 mg, or to achieve a concentration in the GI tract of from about 10 parts per billion to about 50 ppm.
36. The method of claim 31 , wherein the daily dose of the denatonium salt is administered once per day, twice per day or three times per day.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/845,399 US20230096528A1 (en) | 2019-12-24 | 2022-06-21 | Pharmaceutical Composition for Treatment or Prevention of Multiple Inflammatory disorders |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201962953461P | 2019-12-24 | 2019-12-24 | |
US202062971202P | 2020-02-06 | 2020-02-06 | |
US202063022565P | 2020-05-10 | 2020-05-10 | |
US202063092453P | 2020-10-15 | 2020-10-15 | |
PCT/US2020/066835 WO2021133908A1 (en) | 2019-12-24 | 2020-12-23 | Pharmaceutical composition for treatment or prevention of multiple inflammatory disorders |
US17/845,399 US20230096528A1 (en) | 2019-12-24 | 2022-06-21 | Pharmaceutical Composition for Treatment or Prevention of Multiple Inflammatory disorders |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2020/066835 Continuation WO2021133908A1 (en) | 2019-12-24 | 2020-12-23 | Pharmaceutical composition for treatment or prevention of multiple inflammatory disorders |
Publications (1)
Publication Number | Publication Date |
---|---|
US20230096528A1 true US20230096528A1 (en) | 2023-03-30 |
Family
ID=76575137
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/845,399 Pending US20230096528A1 (en) | 2019-12-24 | 2022-06-21 | Pharmaceutical Composition for Treatment or Prevention of Multiple Inflammatory disorders |
Country Status (8)
Country | Link |
---|---|
US (1) | US20230096528A1 (en) |
EP (1) | EP4081201A4 (en) |
JP (1) | JP2023508365A (en) |
KR (1) | KR20230024867A (en) |
CN (1) | CN115243685A (en) |
AU (1) | AU2020414720A1 (en) |
CA (1) | CA3161936A1 (en) |
WO (1) | WO2021133908A1 (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20220193013A1 (en) * | 2020-12-23 | 2022-06-23 | Aardvark Therapeutics Inc. | Pharmaceutical Composition for Treatment or Prevention of Multiple Inflammatory Disorders |
EP4284354A1 (en) * | 2021-02-01 | 2023-12-06 | Aardvark Therapeutics Inc. | Denatonium salt for use in preventing, preventing progression and treating fatty liver diseases |
TW202333657A (en) | 2021-10-14 | 2023-09-01 | 美商艾爾德瓦克治療公司 | Monohydrate salt of denatonium acetate |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070149451A1 (en) * | 2003-11-17 | 2007-06-28 | Holmes David G | Combination of a dpp IV inhibitor and an antiobesity or appetite regulating agent |
US7928132B2 (en) * | 2004-08-06 | 2011-04-19 | Ohio University | Methods for the amelioration of episodes of acute or chronic ulcerative colitis |
PT2661266T (en) * | 2011-01-07 | 2020-11-30 | Anji Pharma Us Llc | Chemosensory receptor ligand-based therapies |
CN102871993A (en) * | 2011-07-11 | 2013-01-16 | 萧湘 | Novel application of bitter |
EP3138899A1 (en) * | 2015-09-04 | 2017-03-08 | The Procter and Gamble Company | Unitary dose detergent articles comprising aversive or bittering agents in part of wrapping water-soluble material and methods related thereto |
US10835505B2 (en) * | 2018-06-11 | 2020-11-17 | Aardvark Therapeutics, Inc. | Oral pharmaceutical formulation for weight loss, diabetes and related disorders |
WO2020014494A1 (en) * | 2018-07-11 | 2020-01-16 | Aardvark Therapeutics Inc. | Oral pharmaceutical formulations of bitter compounds for pulmonary hypertension |
-
2020
- 2020-12-23 KR KR1020227025219A patent/KR20230024867A/en unknown
- 2020-12-23 WO PCT/US2020/066835 patent/WO2021133908A1/en unknown
- 2020-12-23 AU AU2020414720A patent/AU2020414720A1/en active Pending
- 2020-12-23 JP JP2022538819A patent/JP2023508365A/en active Pending
- 2020-12-23 CA CA3161936A patent/CA3161936A1/en active Pending
- 2020-12-23 EP EP20908095.1A patent/EP4081201A4/en active Pending
- 2020-12-23 CN CN202080089539.2A patent/CN115243685A/en active Pending
-
2022
- 2022-06-21 US US17/845,399 patent/US20230096528A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
WO2021133908A1 (en) | 2021-07-01 |
CA3161936A1 (en) | 2021-07-01 |
KR20230024867A (en) | 2023-02-21 |
CN115243685A (en) | 2022-10-25 |
AU2020414720A1 (en) | 2022-07-14 |
JP2023508365A (en) | 2023-03-02 |
EP4081201A4 (en) | 2024-01-10 |
EP4081201A1 (en) | 2022-11-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20230096528A1 (en) | Pharmaceutical Composition for Treatment or Prevention of Multiple Inflammatory disorders | |
IL266915B2 (en) | Dose escalation enzyme replacement therapy for treating acid sphingomyelinase deficiency | |
CN108697703A (en) | Use the method for FXR agonists | |
Kuru et al. | Effect of different enteral nutrients on bacterial translocation in experimental obstructive jaundice | |
US11052073B1 (en) | Sphingosine kinase 2 inhibitor for treating coronavirus infection | |
CN108697704A (en) | Use the method for FXR agonists | |
EP3810122A1 (en) | Compositions and methods for the reduction or treatment of insulin resistance and metabolic conditions | |
US20170224727A1 (en) | Method for regulation of lipid metabolism | |
US9642875B2 (en) | Compounds and their effects on appetite control and insulin sensitivity | |
Lee et al. | Downregulation of IL-18 expression in the gut by metformin-induced gut microbiota modulation | |
TWI671017B (en) | Application of the combination package in the preparation of a medicine for improving and treating human chubby Willie syndrome | |
US11331329B2 (en) | Fucosylated oligosaccharides for prevention of coronavirus infection | |
WO2021191312A1 (en) | Methods of treating covid-19 with rifaximin | |
CN116531410B (en) | Application of staphylococcus albus in preparation of composition | |
US20220193013A1 (en) | Pharmaceutical Composition for Treatment or Prevention of Multiple Inflammatory Disorders | |
US20230234923A1 (en) | Using adiponectin receptor agonists to treat inflammation and bone diseases in diabetes | |
JP2022508167A (en) | Use of glutarimide derivatives for overcoming steroid resistance and treating diseases associated with abnormal interferon gamma signaling | |
JP2023550994A (en) | Nicotinamide, nicotinamide precursors and nicotinamide metabolites and compositions thereof for reducing the time to resolution of symptoms in patients with COVID-19 and other viral infections | |
TW202203934A (en) | Receptor-interacting protein kinase inhibitors for treating conditions involving systemic hyperinflammatory response | |
EP4103192A1 (en) | Compositions and methods for treating coronavirus infections | |
US20230149328A1 (en) | Method for Treating SARS and Treating or Preventing ARDS | |
CN117243938A (en) | Betaine for preventing obesity | |
US20230000845A1 (en) | Biomarkers of coronavirus pneumonia | |
US20190142786A1 (en) | Methods of treating obesity in responder and non-responder populations | |
WO2024038186A1 (en) | Treatment of acute respiratory failure |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |